Proposed Re-evaluation Decision PRVD2019-10
Pyriproxyfen and Its
Associated End-use
Products
Consultation Document
(publié aussi en français) 6 November 2019
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H113-27/2019-10E-PDF (PDF version)
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Proposed Re-evaluation DecisionPRVD2019-10
Table of Contents
Proposed Re-evaluation Decision ................................................................................................... 1
Outcome of Science Evaluation................................................................................................... 1
Proposed Regulatory Decision for Pyriproxyfen ......................................................................... 2
International Context ................................................................................................................... 2
Next Steps .................................................................................................................................... 3
Science Evaluation .......................................................................................................................... 4
1.0 Introduction ......................................................................................................................... 4
2.0 Technical Grade Active Ingredient ..................................................................................... 4
2.1 Identity ........................................................................................................................ 4
2.2 Physical and Chemical Properties .............................................................................. 4
2.3 Description of Registered Pyriproxyfen Uses ............................................................. 5
3.0 Human Health Assessment ................................................................................................. 5
3.1 Toxicology Summary ................................................................................................. 5
3.1.1 Pest Control Products Act Hazard Characterization .................................................. 9
3.2 Dietary Exposure and Risk Assessment ................................................................... 10
3.2.1 Determination of Acute Reference Dose .................................................................. 11
3.2.2 Acute Dietary Exposure and Risk Assessment ......................................................... 11
3.2.3 Determination of Acceptable Daily Intake ................................................................ 11
3.2.4 Chronic Dietary Exposure and Risk Assessment ...................................................... 12
3.2.5 Cancer Assessment ................................................................................................... 13
3.3 Exposure from Drinking Water ................................................................................ 13
3.4 Occupational and Non-Occupational Exposure and Risk Assessment ..................... 13
3.4.1 Toxicology Reference Values ................................................................................... 13
3.4.2 Residential Exposure and Risk Assessment ............................................................. 14
3.4.3 Occupational Exposure and Risk Assessment .......................................................... 17
3.5 Aggregate Exposure and Risk Assessment ............................................................... 20
3.5.1 Toxicology Reference Values for Aggregate Risk Assessment ................................ 21
3.5.2 Residential and Dietary Aggregate Exposure and Risk Assessment ........................ 21
3.6 Cumulative Assessment ............................................................................................ 22
3.7 Incident Reports ........................................................................................................ 22
4.0 Environmental Assessment ............................................................................................... 23
4.1 Fate and Behaviour in the Environment ................................................................... 23
4.2 Environmental Risk Characterization ....................................................................... 23
4.2.1 Risks to Terrestrial Organisms .................................................................................. 23
4.2.2 Risks to Aquatic Organisms ...................................................................................... 24
4.2.3 Environmental Incident Reports ............................................................................... 24
5.0 Value Assessment ............................................................................................................. 24
6.0 Pest Control Product Policy Considerations ..................................................................... 25
6.1 Assessment of the Active Ingredient under the Toxic Substances Management
Policy ........................................................................................................................ 25
6.2 Formulants and Contaminants of Health or Environmental Concern ...................... 25
7.0 Conclusion of Science Evaluation .................................................................................... 26
List of Abbreviations .................................................................................................................... 27
Appendix I Lists of Pyriproxyfen Products and Uses .............................................................. 29
Proposed Re-evaluation DecisionPRVD2019-10
Table 1 Registered Pyriproxyfen Products in Canada as of 1 May 2019 excluding
discontinued products or products with a submission for discontinuation ............... 29
Table 2 Registered Commercial and Restricted Class Uses of Pyriproxyfen as of 1 May 2019
excluding discontinued products or products with a submission for
discontinuation.......................................................................................................... 32
Table 3 Registered Domestic Class Uses of Pyriproxyfen as of 1 May 2019, excluding
discontinued products or products with a submission for discontinuation1 ............. 33
Appendix II Toxicological Information for Health Risk Assessment ....................................... 38
Table 1 Chemical Names of Pyriproxyfen and Select Metabolites ....................................... 38
Table 2 Summary of Toxicology Studies for Pyriproxyfen ................................................... 38
Table 3 Reference Values for Use in Human Health Risk Assessment for Pyriproxyfen ..... 50
Appendix III Dietary Exposure and Risk Assessments .......................................................... 52
Food Residue Chemistry Summary .............................................................................................. 53
Appendix IV Occupational Mixer/Loader/Applicator and Postapplication Risk Assessment 54
Table 1 Occupational Mixer/Loader/Applicator Exposure and Risk Assessment ................ 54
Table 2 Occupational Postapplication Exposure and Risk Assessment ................................ 54
Appendix V Residential Applicator and Postapplication Risk Assessment .............................. 56
Table 1 Residential Applicator Exposure and Risk Assessment ........................................... 56
Table 2 Residential Postapplication Dermal Exposure and Risk Assessment ...................... 56
Table 3 Residential Postapplication Incidental Oral Exposure and Risk Assessment for
Children (1<2 Years old) .......................................................................................... 58
Appendix VI Aggregate Risk Assessment .............................................................................. 59
Table 1 Aggregate Exposure and Risk Assessment ............................................................... 59
Appendix VII Label Amendments for Products Containing Pyriproxyfen .............................. 60
References ..................................................................................................................................... 65
Proposed Re-evaluation Decision - PRVD2019-10
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Proposed Re-evaluation Decision
Under the authority of the Pest Control Products Act, all registered pesticides must be regularly
re-evaluated by Health Canada’s Pest Management Regulatory Agency (PMRA) to ensure that
they continue to meet current health and environmental standards and continue to have value.
The re-evaluation considers data and information from pesticide manufacturers, published
scientific reports, and other regulatory agencies. Health Canada applies internationally accepted
risk assessment methods as well as current risk management approaches and policies.
Pyriproxyfen is an insect growth regulator that contributes to the management of white flies in
greenhouse vegetable and ornamental production, flea control in indoor, non-food areas of
structures and management of fleas on cats and dogs. Commercial products are formulated as
solutions, and are applied by ground application equipment by greenhouse workers and
professional applicators. Domestic-class indoor products are applied to indoor environments as a
trigger pump sprayer or pressurized product. Domestic-class pet treatment products are applied to
dogs as a shampoo, or to dogs and cats as a spot-on treatment. Currently registered products
containing pyriproxyfen can be found in the Pesticide Label Search and in Appendix I.
This document presents the proposed regulatory decision for the re-evaluation of pyriproxyfen
including the proposed risk mitigation measures to further protect human health and the
environment, as well as the science evaluation on which the proposed decision was based. All
products containing pyriproxyfen registered in Canada are subject to this proposed re-evaluation
decision. This document is subject to a 90-day public consultation period, during which the
public including the pesticide manufacturers and stakeholders may submit written comments and
additional information to the PMRA. The final re-evaluation decision will be published taking
into consideration the comments and information received.
Outcome of Science Evaluation
Pyriproxyfen contributes to the management of white flies in greenhouse vegetable and
ornamental production, flea control in indoor, non-food areas of structures and management of
fleas on cats and dogs.
With respect to human health, dietary, residential and aggregate risks from the use of
pyriproxyfen and associated end-use products have been shown to be acceptable. Occupational
risks have been shown to be acceptable with label statements updated to standard baseline
personal protective equipment. For indoor uses to control fleas and ticks, label amendments are
proposed to standardize precautionary statements, to add best practice statements as per
Regulatory Proposal PRO2018-04, Structural Pest Control Products: Label Updates and to
clarify label directions to reflect actual use conditions.
When used according to the proposed label directions, potential risks to the environment from
the use of pyriproxyfen and associated end-use products have been shown to be acceptable.
Proposed Re-evaluation Decision - PRVD2019-10
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Proposed Regulatory Decision for Pyriproxyfen
An evaluation of available scientific information found that all uses of pyriproxyfen products
meet current standards for protection of human health and the environment when used according
to proposed label directions. Under the authority of the Pest Control Products Act, Health
Canada is proposing that products containing pyriproxyfen are acceptable for continued
registration in Canada.
Registered pesticide product labels include specific directions for use. Directions include risk
mitigation measures to protect human health and the environment and must be followed by law.
No products or uses are proposed for cancellation. The proposed label amendments are
summarized below. Refer to Appendix VII for details.
Human Health
To protect mixer/loaders and applicators, updated label statements for personal protective
equipment are proposed.
Label statements are also proposed to address the following:
o Preventing recycled greenhouse water from being applied to outdoor food crops
o Prevent contamination of food and food surfaces during indoor applications
o Clarifying and/or ensuring consistency regarding use directions and precautionary
statements.
o Adding best practice label statements as per PRO2018-04, Structural Pest Control
Products: Label Updates
Due to lack of data to assess occupational exposure, label statements prohibiting
application using handheld mist blower or handheld fogging equipment are proposed.
Environment
Standard label statements to inform users of the potential toxic effects of pyriproxyfen to
aquatic organisms are proposed.
International Context
Pyriproxyfen is currently acceptable for use in other Organisation for Economic Co-operation
and Development (OECD) member countries, including the United States, the European Union,
and Australia.
As of 11 March 2019, no decision by an OECD member country to prohibit all uses of
pyriproxyfen for health or environmental reasons has been identified.
Proposed Re-evaluation Decision - PRVD2019-10
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Next Steps
The public including the registrants and stakeholders are encouraged to submit comments during
the 90-day public consultation period1 upon publication of this proposed re-evaluation decision.
All comments received during the 90-day public consultation period will be taken into
consideration in preparation of re-evaluation decision document,2 which could result in revised
risk mitigation measures. The re-evaluation decision document will include the final re-
evaluation decision, the reasons for it and a summary of comments received on the proposed re-
evaluation decision with Health Canada’s responses.
Additional Scientific Information
No additional information is required at this time.
1 “Consultation statement” as required by subsection 28(2) of the Pest Control Products Act.
2 “Decision statement” as required by subsection 28(5) of the Pest Control Products Act.
Proposed Re-evaluation Decision - PRVD2019-10
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Science Evaluation
1.0 Introduction
2.0 Technical Grade Active Ingredient
2.1 Identity
Common name
Pyriproxyfen
Function
Insect Growth Regulator
Chemical Family
pyridine-based pesticide
Chemical name
1
International Union of Pure
and Applied Chemistry
(IUPAC)
rac-2-{[(2R)-1-(4-phenoxyphenoxy)propan-2-
yl]oxy}pyridine
2
Chemical Abstracts Service
(CAS)
2-[1-methyl-2-(4-
phenoxyphenoxy)ethoxy]pyridine
CAS Registry Number
95737-68-1
Molecular Formula
C20H19NO3
Structural Formula
NOO
CH
3
O
Molecular Weight
321.37 g/mol
Purity of the Technical Grade Active
Ingredient
98.7%
Registration Number
25105
2.2 Physical and Chemical Properties
Property
Vapour pressure at 25°C
Ultraviolet (UV) / visible spectrum
max
Solubility in water at 25°C
Proposed Re-evaluation Decision - PRVD2019-10
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Property
n-Octanol/water partition coefficient
Dissociation constant
2.3 Description of Registered Pyriproxyfen Uses
In Appendix I, Table 1 lists all pyriproxyfen products that are registered under the authority of
the Pest Control Products Act. In Appendix I, Table 2 lists all Commercial Class uses for which
pyriproxyfen is presently registered, while in Appendix I, Table 3 lists all Domestic Class uses
for which pyriproxyfen is presently registered.
All uses were supported by the registrant at the time of re-evaluation initiation and were therefore
considered in the health and environmental risk assessments of pyriproxyfen.
3.0 Human Health Assessment
3.1 Toxicology Summary
Pyriproxyfen is a pyridine insecticide that is an analogue of insect juvenile hormone. A detailed
review of the toxicological database for pyriproxyfen was conducted. The database is complete,
consisting of the full array of toxicity studies currently required for hazard assessment purposes.
Most of the studies were carried out in accordance with currently accepted international testing
protocols and Good Laboratory Practices. The scientific quality of the data is high and the
database is considered adequate to characterize the potential health hazards associated with
pyriproxyfen.
Toxicokinetic investigations were conducted in rats following gavage administration of phenyl-
or pyridyl-radiolabelled pyriproxyfen. Administration of a single low dose of pyriproxyfen
resulted in rapid but low absorption. Males showed higher peak concentrations in blood than
females in the first 24 hours after administration. Maximum tissue concentrations were observed
at eight hours post-dosing with highest concentrations in the liver, blood, kidneys and adipose
tissue. In rats receiving single low, single high or repeated low doses, the highest tissue
concentrations at seven days post-dosing were observed in adipose tissue with other tissues
showing negligible amounts. Pyriproxyfen was extensively and rapidly eliminated in the feces of
rats within 48 hours. Minor amounts of the administered radioactivity were eliminated in urine,
with negligible amounts in expired air. There were no differences in tissue distribution or
elimination attributable to sex, dose level, dosing regimen or position of radiolabel. Fecal
metabolites consisted primarily of 4'-OH-pyr with lesser amounts of unchanged pyriproxyfen.
Minor fecal metabolites included 5"4'-OH-pyr and, depending on the position of the radiolabel,
POPA, 2'-OH-pyr, 5"-OH-pyr, DPH-pyr and sulfate and glucuronide conjugates of some of the
identified metabolites. Unchanged pyriproxyfen and 4'-OH-pyr were either absent, or seen in
minor amounts in the urine of treated rats. Other urinary metabolites, all representing less than
5% of the administered dose, included PYPAC and sulfate conjugates. Chemical names of the
metabolites that were further characterized can be found in Appendix II, Table 1.
Proposed Re-evaluation Decision - PRVD2019-10
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The major pathway of pyriproxyfen metabolism in rats involves hydroxylation at the 4'-position
of the terminal phenyl ring. Minor pathways include hydroxylation at the 2'-position of the
terminal phenyl ring and at the 5"-pyridyl position, dephenylation, cleavage of ether linkages, and
formation of glucuronide and sulfate conjugates. There were no significant effects of sex or dose
on the metabolic pattern of pyriproxyfen in rats. With repeated dosing, the amount of metabolite
produced by oxidation at the 4' position was significantly greater in females as compared to
males.
Pyriproxyfen was of low acute toxicity in rats when administered via the oral and dermal routes
of exposure and of slight acute toxicity via the inhalation route. Clinical signs of toxicity
following acute oral exposure included diarrhea, soft feces and reduced spontaneous activity.
Transient clinical signs following acute inhalation exposure included salivation and urinary
incontinence. Pyriproxyfen was minimally irritating to the eyes and non-irritating to the skin of
rabbits, and was not a dermal sensitizer in guinea pigs in the Maximization assay.
The liver was identified as a target organ throughout the database. In short-term dietary or
capsule administration studies, increased liver weights were seen in rats, mice and dogs;
cytoplasmic changes and increased cholesterol and phospholipids were also noted in rats and
dogs. At high dose levels, dogs also exhibited increased serum enzyme levels, increased
triglycerides, centriacinar fibrosis and bile duct hyperplasia. The kidney was also a target of
toxicity with increased weights in rats and dogs and tubular nephrosis with dilation of the renal
tubules and focal mineralization in mice. The hematological system was affected in the rodent
short-term dietary studies, as demonstrated by decreased red blood cell, hematocrit and
hemoglobin counts. Decreased bodyweight was often concomitant with the observed effects on
the liver, kidney or hematological system.
No treatment-related effects were noted in a short-term dermal toxicity study in rats at the limit
dose of testing (1000 mg/kg bw/day). A NOAEC of 0.48 mg/L was established for rats exposed
via inhalation for four weeks based on transient salivation, decreased bodyweights and absolute
lung weights in males at the limit dose concentration of 1 mg/L.
In a dietary chronic toxicity study in rats, effects included reductions in bodyweight, increases in
liver weight, and transient increases in cholesterol, phospholipids and urinary protein. In a dietary
oncogenicity study in mice, survival was reduced in males, resulting in a study NOAEL of 16
mg/kg bw/day. The primary cause of death was identified as amyloidosis. Although the overall
incidence of amyloidosis in decedents was unaffected by treatment, males that died showed an
increased severity of amyloidosis, particularly of the kidney, thyroid, parathyroid and stomach.
Males and females at a higher dose level showed effects on kidneys (increased incidences of
chronic progressive nephropathy, mineralized tubules), liver (increased weight), and blood
(decreased red blood cells, hemoglobin and hematocrit) as well as decreased bodyweight and
accelerated development and severity of amyloidosis. Reduced survival in females occurred at
this dose level. No treatment-related increase in tumour incidences was evident in either the rat
or mouse studies.
Proposed Re-evaluation Decision - PRVD2019-10
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Pyriproxyfen was negative in a battery of genotoxicity assays including a bacterial reverse
mutation assay, several in vitro assays (mammalian gene mutation assay, unscheduled DNA
synthesis assay and chromosome aberration assay) and an in vivo micronucleus assay.
In the dietary two-generation reproductive toxicity study in rats, there was no evidence of
sensitivity of the young. Increased liver and kidney weights were recorded in F1 males which
progressed to pathological changes at the highest dose level. Decreases in bodyweight during the
pre-mating phase were apparent at the latter level in both generations. Pup bodyweights were
reduced at the highest dose level tested in both generations. There was no effect on reproductive
parameters in the study.
Three gavage developmental toxicity studies in rats were available, assessing different windows
of exposure, namely pre-implantation, during organogenesis, and post-organogenesis through
lactation. No evidence of sensitivity of the young was apparent in these studies. Maternal toxicity
occurred at the same dose level in all three studies and consisted of decreased bodyweight and
food consumption and increased liver and kidney weights. At higher dose levels, mortality was
noted in pregnant dams after several doses during organogenesis or post-organogenesis. No
adverse effects on fetal development were noted at the limit dose in the non-guideline pre-
implantation exposure study; however, a slight decrease in the number of corpora lutea was seen
in the dams at this level. In the study with exposure during organogenesis, an increased incidence
of a variation (opening of the seventh cervical vertebra foramen transversium) was noted in
fetuses. In this study, a subgroup of dams was allowed to deliver their young. Findings in these
offspring at the highest dose level tested included an increased incidence of renal pelvic
dilatation in three and eight-week-old pups and increased kidney weights in eight-week-old pups.
No effects were evident on the sensory function, behavior, motor co-ordination, learning ability
or reproductive performance in pups from this study. In the non-guideline study with
pyrifproxyfen exposure occurring post-organogenesis through lactation, the offspring NOAEL of
100 mg/kg bw/day was based on reduced pup weights at birth and throughout lactation and an
increased incidence of dilatation of the renal pelvis in three-week-old pups. A decrease in pup
viability at postnatal day (PND) 21 was also observed, which was deemed equivocal at this dose
level due to the magnitude of the response. At a higher dose level, pup viability was clearly
affected at birth and throughout the lactation period, reflected in reduced mean litter size. A
slight delay in vaginal opening was also noted in pups at the high-dose level. Increased pre-
implantation loss was observed in high-dose pups that were assessed during adulthood for
reproductive performance, but sensory function, behavior, motor coordination and learning
ability were unaffected by treatment. Overall, the data suggest that the most sensitive window of
exposure was post-organogenesis through lactation; the potential mobilization of pyriproxyfen fat
stores during lactation could play a role in this sensitivity.
In a gavage rabbit developmental toxicity study, maternal toxicity was evident based on the
occurrence of abortions or premature deliveries as well as decreased weight gain with a resultant
NOAEL of 100 mg/kg bw/day. Although the abortions/premature deliveries co-occurred with a
reduction or absence of food intake in the affected dose, it was unknown if this was a causal
factor or merely a correlation with the occurrence of the abortions/premature deliveries.
Proposed Re-evaluation Decision - PRVD2019-10
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At the highest dose level tested (limit dose), additional effects in maternal animals included
weight loss and mortality. Fetal effects were limited to an increased incidence of a variation
(abnormal location of posterior vena cava) at the highest dose level.
There was no evidence of selective neurotoxicity in either the acute gavage or 90-day dietary
neurotoxicity studies in the rat. Effects in the acute neurotoxicity study were limited to a transient
reduction in motor activity on the day of dosing in male animals at a high dose level. Reduced
bodyweight and food consumption were the only effects observed in the 90-day neurotoxicity
study.
No adverse effects were noted in a 28-day dietary immunotoxicity study in mice. A dietary range-
finding study conducted in mice with higher dose levels showed effects on bodyweight as well as
liver and kidney toxicity. Overall, there was no evidence of immune dysregulation.
A battery of endocrine-related studies was conducted for the United States Endocrine Disruptor
Screening Program. In in vitro assays, pyriproxyfen was negative for estrogen and androgen
receptor binding and aromatase inhibition and did not affect testosterone production, but was a
weak inducer of estradiol production in the steroidogenesis assay. Pyriproxyfen did not show
endocrine-related toxicity in either the uterotrophic or Hershberger assays conducted via gavage
in rats. In the female pubertal assay, rats gavage-dosed with pyriproxyfen showed a slight delay
for incomplete vaginal opening and a reduction in females cycling regularly at the limit dose
level concurrent with evidence of hepatic and renal toxicity; the time for complete vaginal
opening was unaffected by treatment. Minimal evidence of thyroid toxicity was present in this
study. In the male pubertal assay, rats gavage-dosed with pyriproxyfen showed decreases in
serum testosterone levels and in the weights of androgen sensitive organs as well as a slight delay
for complete preputial separation. These effects occurred in the presence of hepatic and renal
toxicity. Slight changes in thyroid pathology were also evident in this study but thyroid hormones
were unaffected by treatment. Androgen-related effects (decreased testosterone as well as
weights of androgen-sensitive organs, delayed preputial separation) were also observed in a
mechanistic study in gavage-dosed pubertal male rats. In addition to the co-occurring indicators
of hepatic and renal toxicity in this study (organ weight changes, clinical chemistry alterations
and histopathology), liver enzyme induction was evident. No effect on 17β-hydroxysteroid
dehydrogenase activity in the testis was evident. The data suggest that the potential anti-
androgenic effects could be secondary to the increased metabolism of testosterone by the liver.
Concern was raised in the public domain regarding the relationship between pyriproxyfen and the
increase in microcephaly cases in Brazil in 2015 and 2016. Pyriproxyfen was added to the
drinking water supply to combat the larva of mosquitos that carried the Zika virus. Although the
increase in microcephaly has been strongly correlated with the mosquito-borne Zika virus, one
publication considered a possible link with pyriproxyfen exposure (PMRA #2857241). The
authors speculated that pyriproxyfen has cross-reactivity with retinoic acid, a known
developmental toxicant, but did not provide data to support this claim. The authors cited a
decrease in relative brain weight seen in eight-week-old male pups from dams that received
300 mg/kg bw/day in the rat developmental toxicity study (PMRA #1143907) as supporting
evidence for their concern. This observation was not considered treatment-related by the PMRA
for several reasons including: lack of a dose relationship, lack of a similar response in female
Proposed Re-evaluation Decision - PRVD2019-10
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pups, the lack of an effect on absolute brain weight (considered to be a better measure of
response due to the conserved nature of brain weight) and the lack of a similar observation in the
reproductive toxicity assay.
Results of a published case-control study (PMRA #2857240) did not identify an association
between microcephaly and pyriproxyfen; however, there was a strong association between
microcephaly and the Zika virus. In a published ecological study (PMRA #2857242), there was
no difference in the prevalence of microcephaly between Brazilian municipalities using
pyriproxyfen and those using Bacillus thuringiensis israelensis. Although these epidemiological
studies had limitations, the findings did not support a concern for pyriproxyfen. Results of an
additional published study (PMRA #2857243) did not reveal evidence of brain malformations or
significant changes in the number of stem cells in the developing central nervous system in
zebrafish embryos. The findings in these studies, taken together with the absence of treatment-
related malformations in the developmental and reproductive toxicity studies, do not suggest that
pyriproxyfen was a causal factor in the increase in microcephaly cases in Brazil.
Further data in the scientific literature included two in vitro studies that indicated weak
estrogenic activity, and two in vitro studies that demonstrated cytotoxicity. The findings in these
studies did not substantially impact the current understanding of pyriproxyfen toxicity.
The mammalian metabolites 4'-OH-pyr, 5"-OH-pyr, DPH-pyr, POPA and PYPAC were of low
acute oral toxicity in the mouse and negative in a bacterial reverse mutation assay. Slight acute
oral toxicity in mice and negative findings in a bacterial reverse mutation assay were noted for
2,5-OH-py, a minor metabolite noted in the lactating goat metabolism study. A plant metabolite,
2-OH-py, was of high acute toxicity in the mouse; however, it was considered a minor
metabolite. It was also negative in a bacterial reverse mutation assay.
Results of the toxicology studies conducted on laboratory animals with pyriproxyfen are
summarized in Appendix II, Table 2. The toxicology reference values for use in the human health
risk assessment are summarized in Appendix II, Table 3.
3.1.1 Pest Control Products Act Hazard Characterization
For assessing risks from potential residues in food or from products used in or around homes or
schools, the Pest Control Products Act requires the application of an additional 10-fold factor to
threshold effects to take into account completeness of the data with respect to the exposure of,
and toxicity to, infants and children, and potential prenatal and postnatal toxicity. A different
factor may be determined to be appropriate on the basis of reliable scientific data.
With respect to the completeness of the toxicity database as it pertains to the toxicity to infants
and children, the database contains the full complement of required studies including gavage
developmental toxicity studies in rats and rabbits and a dietary two-generation reproductive
toxicity study in rats. Additional data on the young were available from gavage pubertal assays
conducted in juvenile rats with pyriproxyfen.
Proposed Re-evaluation Decision - PRVD2019-10
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With respect to potential prenatal and postnatal toxicity, there was no indication of increased
sensitivity of fetuses or offspring compared to parental animals in the reproductive and
developmental toxicity studies. Minor developmental effects (increased incidence of fetal
variations) were observed in the rat and rabbit guideline developmental toxicity studies; however,
these effects occurred in the presence of maternal toxicity. A serious effect, abortion/premature
delivery, was noted in maternal animals in the rabbit developmental toxicity study. Each of the
affected animals ceased consuming food and lost weight for several days prior to litter loss. It
was unknown whether the abortions/premature deliveries were the consequence of a direct effect
on the fetus or secondary to overt toxicity in the maternal animal. A reduction in the number of
corpora lutea was noted in rats administered pyriproxyfen prior to the implantation period in a
non-guideline developmental toxicity study; however, this effect was only noted at the limit dose
of testing and in the presence of significant maternal toxicity including mortality. In a non-
guideline developmental toxicity study in rats in which dams were dosed post-organogenesis
through lactation, pups at the mid-dose level exhibited renal effects, decreased weight at birth
and throughout lactation, and an equivocal decrease in viability at PND 21. The equivocal
decrease in viability at this dose level was deemed a low concern due to the small magnitude of
the effect. At a higher dose level, pup effects included clearly reduced viability at birth and
throughout lactation, delayed sexual development and an increase in pre-implantation loss when
these pups were mated at adulthood. In the rat reproductive toxicity study, pup weight was
reduced in both generations at a dose level that resulted in parental toxicity (effects on liver,
kidney and bodyweight). Delayed sexual development was noted in young male and female rats
in the pubertal assays but occurred concurrently with other systemic toxicity (liver, kidney and
bodyweight effects).
Overall, endpoints in the young were well-characterized and there was no evidence of sensitivity.
Endpoints considered serious in nature included the abortions/premature deliveries in rabbits, the
decrease in corpora lutea in rats and the clear effects on rat pup viability. On the basis of this
information, the Pest Control Products Act factor (PCPA factor) was reduced to threefold when
these endpoints were used as the point of departure for risk assessment. In scenarios where other
endpoints were selected, the risk assessment was protective of the serious endpoints and the
PCPA factor was reduced to onefold.
3.2 Dietary Exposure and Risk Assessment
In a dietary exposure assessment, the PMRA determines how much of a pesticide residue,
including residues in meat and milk, may be ingested with the daily diet. Exposure to
pyriproxyfen from potentially treated imported foods is also included in the assessment. Dietary
exposure assessments are age-specific and incorporate the different eating habits of the
population at various stages of life (infants, children, adolescents, adults and seniors). For
example, the assessments take into account differences in children’s eating patterns, such as food
preferences and the greater consumption of food relative to their body weight when compared to
adults. Dietary risk is then determined by the combination of the exposure and the toxicity
assessments. High toxicity may not indicate high risk if the exposure is low. Similarly, there may
be risk from a pesticide with low toxicity if the exposure is high.
Proposed Re-evaluation Decision - PRVD2019-10
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The PMRA considers limiting use of a pesticide when exposure exceeds 100% of the reference
dose. The PMRA’s Science Policy Note SPN2003-03, Assessing Exposure from Pesticides, A
User’s Guide, presents detailed risk assessment procedures.
Residue estimates used in the dietary risk assessment may be based conservatively (in other
words, are high-end estimates) on the maximum residue limits (MRLs) or the field trial data
representing the residues that may remain on food after treatment at the maximum label rate.
Surveillance data representative of the national food supply may also be used to derive a more
accurate estimate of residues that may remain on food when it is purchased. These include the
Canadian Food Inspection Agency’s (CFIA) National Chemical Residue Monitoring Program
and the United States Department of Agriculture Pesticide Data Program (USDA PDP). Specific
and empirical processing factors as well as specific information regarding percent of crops
treated may also be incorporated to the greatest extent possible.
Sufficient information was available to adequately assess the dietary exposure and risk from
pyriproxyfen. The chronic dietary exposure and risk assessments were conducted using the
Dietary Exposure Evaluation Model - Food Commodity Intake Database™ (DEEM-FCID,
Version 4.02, 05-10-c) program which incorporates consumption data from the National Health
and Nutrition Examination Survey/What We Eat in America (NHANES/WWEIA) for the years
2005-2010 available through the Centers for Disease Control and Prevention’s (CDC) National
Center for Health Statistics (NCHS). Further details on the consumption data are available in
Science Policy Note SPN2014-01, General Exposure Factor Inputs for Dietary, Occupational
and Residential Exposure Assessments.
3.2.1 Determination of Acute Reference Dose
An acute reference dose (ARfD) was not required as no endpoint of concern attributable to a
single exposure was identified.
3.2.2 Acute Dietary Exposure and Risk Assessment
An acute dietary exposure and risk assessment was not required.
3.2.3 Determination of Acceptable Daily Intake
To estimate risk from repeated dietary exposure, the mouse oncogenicity study with a NOAEL of
16 mg/kg bw/day was selected. At the LOAEL of 79 mg/kg bw/day, reduced survival and
increased severity of amyloidosis were observed. This study provides the lowest NOAEL in the
database. Standard uncertainty factors of 10-fold for interspecies extrapolation and 10-fold for
intraspecies variability were applied. As discussed in the Pest Control Products Act Hazard
Characterization Section, the PCPA factor was reduced to onefold. The composite assessment
factor (CAF) is thus 100.
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The acceptable daily intake (ADI) is calculated according to the following formula:
ADI = NOAEL = 16 mg/kg bw/day = 0.2 mg/kg bw/day of pyriproxyfen
CAF 100
The ADI provides a margin of 500 or greater to the NOAELs for abortions/premature deliveries
in rabbits and reduced corpora lutea and pup viability in rats.
3.2.4 Chronic Dietary Exposure and Risk Assessment
Generally, the chronic dietary risk is calculated using average consumption of different foods and
the average residue values on those foods. For pyriproxyfen specifically, the average
consumption values were used and the maximum potential residues as noted below were used.
This would result in conservative (high-end) estimates of exposure. The estimated exposure was
then compared to the ADI, which is an estimate of the level of daily exposure to a pesticide
residue that, over a lifetime, is believed to have no significant harmful effects. When the
estimated exposure is less than the ADI, the chronic dietary exposure is shown to be acceptable.
The exposure assessment was conducted using the Canadian maximum residue limits (MRLs) or
American tolerances for pyriproxyfen (whichever was greater). Available CODEX MRLs were
used for commodities without Canadian MRLs or American tolerances. For agricultural crops,
100% crop treated was assumed. Available experimental processing factors were also used in the
assessment.
In the United States, a tolerance of 0.1 ppm pyriproxyfen has been established for all
commodities not listed as having specific American tolerances. This tolerance is intended for
residues on foods resulting from the use of pyriproxyfen products in food handling
establishments. Use of pyriproxyfen in food handling establishments is not a registered use in
Canada. However, in consideration of potential food imports to Canada from the United States,
the American tolerance of 0.1 ppm was used in the dietary exposure assessment for all
commodities for which no MRL or tolerance has been established. For these commodities, 4.65%
were considered to be treated based on percent of food handling establishments treated in the
United States. In addition, commodities with existing Canadian MRLs lower than 0.1 ppm were
assigned the 0.1 ppm for the dietary assessment, since as noted above, the highest value of either
the Canadian MRL or American tolerance was used in the assessment.
CFIA and USDA PDP residue monitoring data for pyriproxyfen were available but were not used
in this assessment; there was no need for this level of residue refinement at this time. The
monitoring data showed non-detect values for the majority of commodities, with only a few
detected residues but at levels lower than the established MRLs or tolerances.
The chronic dietary risk assessment was conducted for the general population and all population
subgroups. The chronic dietary exposure for the general population was approximately 5% of the
ADI. Chronic exposures for population subgroups ranged from approximately 4% of the ADI to
13% of the ADI. Children 1–2 years old were the subpopulation expected to be subject to the
highest exposures relative to bodyweight. Pyriproxyfen dietary risk was, therefore, shown to be
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acceptable for the general population and all population subgroups. For more information on the
dietary risk estimates or the residue chemistry information used in the dietary assessment, see
Appendix III.
Best practice label statements are proposed to clarify label directions as it relates to potential
residues on food as follows:
As there are no field uses of pyriproxyfen, label statements to prevent recycled
greenhouse water from being applied to outdoor food crops;
Label statements to prevent contamination of food and food surfaces during indoor
applications for control of fleas and ticks.
See Appendix VII for specific label statements.
3.2.5 Cancer Assessment
There was no evidence of carcinogenicity and therefore, a cancer risk assessment was not
necessary.
3.3 Exposure from Drinking Water
Given that pyriproxyfen is registered for greenhouse and indoor uses only, exposure of drinking
water sources was deemed minimal and, therefore, drinking water contribution to the dietary
exposure was not considered in this assessment. Label statements are being proposed to prevent
residues from entering drinking water sources. See Appendix VII for specific label statements.
3.4 Occupational and Non-Occupational Exposure and Risk Assessment
Occupational and residential risk is estimated by comparing potential exposures with the most
relevant endpoint from toxicology studies to calculate a margin of exposure (MOE). This is
compared to a target MOE incorporating uncertainty factors protective of the most sensitive
subpopulation. If the calculated MOE is less than the target MOE, it does not necessarily mean
that exposure will result in adverse effects, but mitigation measures to reduce risk would be
required.
3.4.1 Toxicology Reference Values
Short- and Intermediate-Term Dermal and Inhalation
For short- and intermediate-term dermal and inhalation risk assessment for adults, the oral
developmental toxicity study in rabbits was selected. A NOAEL of 100 mg/kg bw/day was
established. At 300 mg/kg bw/day, an increase in abortions/premature deliveries was observed in
the presence of maternal toxicity. Although short-term dermal and inhalation toxicity studies
were available, they were not chosen for reference value selection since the design of those
studies does not allow for the assessment of the relevant endpoint of concern. Standard
uncertainty factors of 10-fold for interspecies extrapolation and 10-fold for intraspecies
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variability were applied. For residential scenarios, as discussed in the Pest Control Products Act
Hazard Characterization Section, the PCPA factor was reduced to threefold, resulting in a target
margin of exposure (MOE) of 300. For occupational scenarios, the target MOE was also 300
reflecting the use of an additional threefold factor for a serious effect in the presence of maternal
toxicity.
For short and intermediate-term dermal and inhalation risk assessment for children, the oral
developmental toxicity study in rats that included a postnatal phase was selected. A NOAEL of
100 mg/kg bw/day was established. At 300 mg/kg bw/day, pup weight was reduced along with an
equivocal reduction in pup viability. Although short-term dermal and inhalation toxicity studies
were available, they were not chosen for reference value selection since the design of those
studies does not allow for the assessment of the relevant endpoint of concern. A target MOE of
100 was established based on standard uncertainty factors of 10-fold for interspecies
extrapolation and 10-fold for intraspecies variability, along with a PCPA factor of onefold, as
discussed in the Pest Control Products Act Hazard Characterization Section.
Long-term Dermal and Inhalation
For long-term dermal and inhalation risk assessment, the mouse oncogenicity study with a
NOAEL of 16 mg/kg bw/day was selected. At the LOAEL of 79 mg/kg bw/day, reduced survival
and increased severity of amyloidosis were observed. Standard uncertainty factors of 10-fold for
interspecies extrapolation and 10-fold for intraspecies variability were applied resulting in a
target MOE of 100. For residential scenarios, the PCPA factor was reduced to onefold as
discussed in the Pest Control Products Act Hazard Characterization Section.
Non-Dietary Oral Ingestion (Children, Short-term)
For non-dietary oral ingestion, the 90-day oral toxicity study in rats with a NOAEL of 24 mg/kg
bw/day in rats was selected for risk assessment. At the LOAEL of 118 mg/kg bw/day, effects
were noted on the liver and hematological system. Standard uncertainty factors of 10-fold for
interspecies extrapolation and 10-fold for intraspecies variability, along with a PCPA factor of
onefold, as discussed in the Pest Control Products Act Hazard Characterization Section, resulted
in a target MOE of 100.
Dermal Absorption
No chemical-specific dermal absorption studies were submitted to the PMRA. Therefore, dermal
absorption of 100% was used in the risk assessment.
3.4.2 Residential Exposure and Risk Assessment
Residential risk assessment involves estimating risks to the general population, including
children, during or after pesticide application.
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The USEPA has generated standard default assumptions for developing residential exposure
assessments for both applicator and postapplication exposures when chemical- and/or site-
specific field data are limited. These assumptions may be used in the absence of, or as a
supplement to, chemical- and/or site-specific data and generally result in high-end estimates of
exposure. These assumptions are outlined in the Standard Operating Procedures (SOP) for
Residential Pesticide Exposure Assessments (USEPA, 2012).
The following sections from the USEPA Residential SOPs were used to assess residential
exposure to pyriproxyfen:
Section 7: Indoor Environments
Section 8: Treated Pets
3.4.2.1 Residential Applicator Exposure and Risk Assessment
Residential applicators are adults who apply domestic-class pyriproxyfen products that are
registered for use inside the home. Applicators are assumed to be adults (>16 years old) and to
wear shorts, short-sleeved shirts, shoes and socks.
There is potential exposure to residential applicators applying pyriproxyfen inside homes and to
pets (dogs and cats). Based on typical use patterns, the representative scenarios identified were:
Applying pressurized product formulations to indoor environments
Applying liquid formulations using ready-to-use trigger pump sprayers to indoor
environments
Applying liquid formulations as a shampoo to dogs
Applying liquid formulations using a ready-to-use spot-on application to dogs and cats
Residential applicators have the potential for short-to-intermediate term exposure (<6 months)
due to seasonality of the pests listed on the label (for example, fleas, ticks and mosquitoes).
Route-specific MOEs for residential applicators are outlined in Appendix V, Table 1. Calculated
MOEs for dermal, inhalation, and combined (dermal + inhalation) exposures for residential
applicators of pyriproxyfen exceeded target MOEs for all scenarios, and therefore, risks were
shown to be acceptable.
3.4.2.2 Residential Postapplication Exposure and Risk Assessment
Residential postapplication exposure refers to an exposure scenario in which an individual is
exposed through dermal, inhalation, and/or incidental oral (non-dietary ingestion) routes as a
result of being in a residential environment or contacting a surface that has been previously
treated with a pesticide. The surface could have been treated by a residential applicator using a
domestic-class product or a commercial applicator hired to treat the residential area.
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There is potential for intermittent, short- to intermediate-term exposure to adults and children
through contact with transferable residues following application of pyriproxyfen to indoor
environments and to pets. Adults and children have the potential for postapplication dermal
exposure; children aged 1 to <2 years old also have the potential for incidental oral exposure.
Since children aged 1 to 2 years have the greatest potential for exposure, risk outcomes for this
population of children are presented. Inhalation exposure is considered to be minimal compared
to dermal exposure, since pyriproxyfen has a low vapour pressure and meets the criteria for an
inhalation waiver based on low volatility. Thus, a residential postapplication inhalation exposure
assessment was not required.
The following scenarios were assessed for residential use of products containing pyriproxyfen:
Indoor Environments:
o Adults and children (1 to <2 years old) dermal exposure resulting from activities
indoors.
o Incidental oral (hand-to-mouth, object-to-mouth) exposure to children (1 to <2
years old) in indoor environments.
Treated Pets:
o Adults and children (1 to <2 years old) dermal exposure resulting from activities
with treated pets.
o Incidental oral (hand-to-mouth) exposure to children (1 to <2 years old) from
treated pets.
The highest application rate was used in the postapplication risk assessment for pyriproxyfen. It
is assumed that individuals contact previously treated surfaces and pets on the same day the
pesticide treatment is applied. Multiple applications were not assessed for indoor and pet uses of
pyriproxyfen since exposure on the day of application (Day 0) without any dissipation was
assumed for the entire duration of exposure. These assumptions would result in conservative or
high-end estimates of exposure.
Dermal Exposure
Postapplication dermal exposure was calculated using activity-specific transfer coefficients, for
treated surfaces or treated pet fur, dislodgeable residue (residue transfer to skin) and exposure
time. A transfer coefficient is a factor that relates exposure to dislodgeable residues and the
amount of treated surface that a person contacts while performing activities in a given time
period (usually expressed in units of cm2 per hour). It is specific to a particular population and
activity/location (for example, children playing on soft surfaces such as carpets).
Calculated dermal MOEs for residential postapplication exposure to pyriproxyfen exceeded
target MOEs for all populations and scenarios, and therefore, risks are shown to be acceptable.
The residential dermal postapplication risk assessment is outlined in Appendix V, Table 2.
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Incidental Oral Exposure
Postapplication incidental oral exposure assumes that pesticide residues are transferred to the
skin of children’s (1 to <2 years old) hands while playing on treated indoor surfaces or with
treated pets, and are subsequently ingested as a result of hand-to-mouth transfer. For indoor
applications, residues that could result on children’s toys and which could subsequently be
ingested as a result of mouthing activity with the toy are also considered (object-to-mouth
transfer).
Calculated incidental oral MOEs for residential postapplication exposure to pyriproxyfen
exceeded target MOEs, and therefore, risks are shown to be acceptable. The residential incidental
oral postapplication risk assessment is outlined in Appendix V, Table 3.
3.4.2.3 Label Statements
For end-use products with directions for indoor uses to control fleas and ticks, label amendments
are proposed as follows:
Clarifying and/or ensuring consistency regarding use directions and precautionary
statements.
Adding best practice label statements as per PRO2018-04, Structural Pest Control
Products: Label Updates.
See Appendix VII for specific label statements for pyriproxyfen.
3.4.3 Occupational Exposure and Risk Assessment
There is potential for exposure to pyriproxyfen in occupational scenarios from workers handling
the pesticide during the application process, and potential for postapplication exposure from
workers entering into areas or handling pets previously treated with pyriproxyfen.
3.4.3.1 Mixer, Loader, and Applicator Exposure and Risk Assessment
There are potential exposures to mixers, loaders, and applicators. The following scenarios were
assessed:
Application to greenhouse crops
Application in indoor structures, including homes, using the commercial-class product
Application of domestic-class spot-on or shampoo products to pets by workers
Typically, it is assumed that commercial applicators or workers would not be using domestic-
class products. However, for pyriproxyfen, since there are no commercial-class products
registered for application to pets, it was assumed that workers would be using domestic-class
products (for example, in veterinary clinics).
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Greenhouse and Indoor Structures
For greenhouse and indoor structures, the following application equipment were assessed:
Backpack application to greenhouse ornamentals, tomatoes, cucumbers, peppers and
eggplants
Manually-pressurized handwand application to indoor structures and greenhouse
ornamentals, tomatoes, cucumbers, peppers and eggplants
Mechanically-pressurized handgun application to greenhouse ornamentals, tomatoes,
cucumbers, peppers and eggplants
Farmers and commercial applicators may handle pyriproxyfen for short to intermediate periods of
time depending on the crop and use site. Therefore, the short-to-intermediate endpoints were
used for all scenarios.
Exposure was estimated for baseline personal protective equipment (PPE): long pants, long-
sleeved shirt, chemical-resistant gloves, socks and shoes.
No appropriate chemical-specific handler exposure data were available for pyriproxyfen.
Therefore, dermal and inhalation exposures were estimated using data from the Pesticide
Handlers Exposure Database Version 1.1 (PHED). PHED is a compilation of generic
mixer/loader applicator passive dosimetry data with associated software that facilitates the
generation of scenario-specific exposure estimates based on formulation type, application
equipment, mix/load systems and level of PPE.
In addition, for application to indoor structures, a passive dosimetry study that monitored
exposure of pest control operators (PCOs) applying liquid products indoors as a surface spray
using a manually-pressurized handwand was used.
Data were not available to assess exposures when using handheld mist blower or handheld
fogging equipment. Therefore, label statements prohibiting application with these equipment are
proposed.
Route-specific MOEs for mixer/loaders and applicators are outlined in Appendix IV, Table 1.
Calculated MOEs from dermal, inhalation, and combined (dermal + inhalation) routes for
mixer/loaders and applicators of pyriproxyfen exceeded target MOEs for all scenarios, and
therefore, risks are shown to be acceptable.
Since the assessment was conducted with handlers wearing baseline PPE, label statements are
proposed to be added to labels currently lacking this PPE. Specifically, to protect mixer/loaders
and applicators applying in indoor environments to control fleas, baseline PPE is proposed.
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Application to Pets
There are no specific exposure data for commercial handlers (for example, veterinarians,
groomers) using domestic-class spot-on or shampoo products to treat pets. Therefore, exposure
was compared to the residential applicator in terms of amount of product handled, number of pets
treated, PPE worn, and margins of exposure. For commercial users, the extent of exposure is
uncertain; however, these workers typically wear PPE when applying pet products, such as a
laboratory coat/apron. The number of animals treated per day by a worker with spot-on or
shampoo products in animal facilities may be higher than for residential applicators treating their
own pets. However, it was assumed that applying pet products is only one of many tasks that
workers would do in a typical day, and it may not always be the same product being applied.
Risks were shown to be acceptable for residential applicators (see Section 3.4.2), and based on
the exposure considerations above, risks are expected to be acceptable for commercial users as
well.
3.4.3.2 Postapplication Worker Exposure and Risk Assessment
There is potential exposure to workers entering treated sites or handling treated pets. Possible
occupational postapplication worker scenarios include:
Agriculture: Workers entering treated greenhouses to conduct agronomic activities
Indoor Structures: Workers entering treated commercial, industrial or institutional
locations
Pet Uses: Veterinarians or other workers handling treated pets.
No chemical-specific data were available to assess postapplication exposure to workers.
Agriculture
The postapplication occupational risk assessment considered exposures to workers who enter
treated sites to conduct agronomic activities involving foliar contact (for example, scouting).
Based on the use of pyriproxyfen in greenhouse crops, there is potential for long-term
postapplication exposure to pyriproxyfen residues for workers.
Potential exposure to postapplication workers was estimated using updated activity-specific
transfer coefficients (TCs), and default dislodgeable foliar residue (DFR) values, since chemical-
specific DFR data were not available (see below). The DFR refers to the amount of residue that
can be dislodged or transferred from a surface, such as leaves of a plant. The TC is a measure of
the relationship between exposure and DFRs for individuals engaged in a specific activity, and is
calculated from data generated in field exposure studies. The TCs are specific to a given crop and
activity combination, and reflect standard agricultural work clothing worn by adult workers.
Activity-specific TCs from the Agricultural Re-entry Task Force (ARTF) were used.
Postapplication exposure activities for agricultural crops include (but are not limited to):
harvesting, weeding and scouting.
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For more information about estimating worker postapplication exposure, refer to the PMRA’s
Regulatory Proposal PRO2014-02, Updated Agricultural Transfer Coefficients for Assessing
Occupational Postapplication Exposure to Pesticides.
Since no acceptable chemical-specific DFR studies were available for pyriproxyfen, default
values were used (peak DFR of 25% of the application rate for all crops). For further information
on these default values, refer to the PMRA’s Science Policy Note SPN2014-02, Estimating
Dislodgeable Foliar Residues and Turf Transferable Residues in Occupational and Residential
Postapplication Exposure Assessments.
For workers entering a treated site, restricted-entry intervals (REIs) are calculated to determine
the minimum length of time required before people can safely enter after application. An REI is
the duration of time that must elapse before residues decline to a level where performance of a
specific activity results in exposures above the target MOE.
Postapplication exposure would be primarily via the dermal route. Based on the vapour pressure
of pyriproxyfen, inhalation exposure would be low, provided that the minimum 12-hour REI is
followed.
The postapplication exposure assessment is outlined in Appendix IV, Table 2. At a 12-hour REI,
postapplication risks to workers performing activities such as thinning, pruning, and harvesting,
were shown to be acceptable.
Indoor Structures and Pet Uses
For indoor structural uses and for pet uses, there is potential for short- to intermediate-term
exposure for workers entering treated areas or handling treated pets.
Exposure for postapplication workers in these scenarios was assessed qualitatively. It was
assumed that risks to postapplication workers in these scenarios would be similar to or less than
residential postapplication risks, since time spent in residential areas or time spent handling pets
in the home is assumed to be longer than the respective times in workplaces. Risks were shown
to be acceptable for residential postapplication scenarios for adults after commercial applications
in homes and after handling treated pets (see Section 3.4.2). Based on the exposure
considerations above, risks are expected to be acceptable for workers as well.
3.5 Aggregate Exposure and Risk Assessment
Aggregate exposure is the total exposure to a single pesticide that may occur from food, drinking
water, residential, and other non-occupational sources, and from all known or plausible exposure
routes (oral, dermal and inhalation).
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3.5.1 Toxicology Reference Values for Aggregate Risk Assessment
Short- and Intermediate-term Aggregate
For short- and intermediate-term aggregate assessment for adults, the oral developmental toxicity
study in rabbits was selected. A NOAEL of 100 mg/kg bw/day was established. At 300 mg/kg
bw/day, an increase in abortions/premature deliveries was observed in the presence of maternal
toxicity. This finding was considered relevant for all routes of exposure. Standard uncertainty
factors of 10-fold for interspecies extrapolation and 10-fold for intraspecies variability, along
with a PCPA factor of threefold, as discussed in the Pest Control Products Act Hazard
Characterization Section, resulted in a target MOE of 300.
For short and intermediate-term aggregate assessment for children, the oral developmental
toxicity study in rats that included a postnatal phase was selected. A NOAEL of 100 mg/kg
bw/day was established. At 300 mg/kg bw/day, pup weight was reduced along with an equivocal
reduction in pup viability. This finding was considered relevant for all routes of exposure.
Standard uncertainty factors of 10-fold for interspecies extrapolation and 10-fold for intraspecies
variability, along with a PCPA factor of onefold, as discussed in the Pest Control Products Act
Hazard Characterization Section, resulted in a target MOE of 100.
3.5.2 Residential and Dietary Aggregate Exposure and Risk Assessment
In an aggregate risk assessment, the combined potential risk associated with food, drinking water
and various residential exposure pathways is assessed. A major consideration is the likelihood of
co-occurrence of exposures and durations of exposures.
Aggregate assessments were conducted for the following short-to-intermediate term scenarios
which are expected to co-occur:
Following commercial application to control fleas in residential areas:
o Postapplication dermal exposure to adults and children + incidental oral exposure
to children + dietary exposure (food only) for adults and children
Following application of a domestic-class product indoors to control fleas and ticks:
o For adults, applicator dermal and inhalation exposure + postapplication dermal
exposure + dietary exposure (food only)
o For children, postapplication dermal exposure + incidental oral exposure +
dietary exposure (food only)
Following application of a domestic-class product to pets:
o For adults, applicator dermal and inhalation exposure + postapplication dermal
exposure + dietary exposure (food only)
o For children, postapplication dermal exposure + incidental oral exposure +
dietary exposure (food only)
Calculated MOEs for aggregate exposure to pyriproxyfen exceeded target MOEs and therefore,
risk is shown to be acceptable. The aggregate risk assessment is outlined in Appendix VI,
Table 1.
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3.6 Cumulative Assessment
The Pest Control Products Act requires that the PMRA considers the cumulative exposure to
pesticides with a common mechanism of toxicity. For the current re-evaluation, the PMRA did
not identify information indicating that pyriproxyfen shares a common mechanism of toxicity
with other pest control products. Therefore there is no requirement for a cumulative risk
assessment at this time.
3.7 Incident Reports
As of 6 December 2018, the PMRA had received 73 human and 6058 domestic animal incidents
involving pyriproxyfen. The pyriproxyfen products reported in incidents are mostly co-
formulated with other active ingredients (for example, synthetic pyrethroids, pyrethrins,
imidacloprid).
Forty-nine human incidents were considered to be possibly related to the reported pyriproxyfen
product. The co-formulated pyriproxyfen products reported in incidents involved companion
animal spot-on products and indoor sprays or foggers. Minor skin and eye irritation were the
most common signs in people and the reported exposure scenarios include treating pets, coming
in contact with treated pets or indoor areas, and during product application. There were six
serious American incidents with co-formulated pyriproxyfen products. Signs reported in these
incidents include effects such as temporary blindness, respiratory distress or muscular weakness.
The described exposure scenarios include ocular exposure when treating a pet, excessive
application of a pesticide, applying a product in non-ventilated areas or living in treated areas. In
one serious American incident involving cardiac arrest and death, the label directions of the
American product were not followed.
The domestic animal incidents mainly involved spot-on pyriproxyfen products registered for use
on cats and dogs (5967 reports). The review of spot-on incidents involving pyriproxyfen and the
proposed mitigation measures for all spot-on products are discussed under Regulatory Proposal
PRO2018-01, Consultation on Proposed Regulatory Changes for Pesticide Products Used on
Companion Animals. Of the remaining 91 incidents, the majority were considered to be possibly
related to the reported pyriproxyfen product. Three minor incidents occurred in the Canada, while
the remainder were serious American incidents mainly involving cats. The reported exposure
scenarios include treatment with an American shampoo containing a pyriproxyfen formulation
not registered for use in Canada or exposure to an indoor spray/powder. The minor signs reported
in animals include symptoms such as drooling, lethargy, anorexia or vomiting. In animals that
died, reported signs include more serious effects like ataxia or convulsion.
Overall, the review of incident reports suggests that the synthetic pyrethroids and/or pyrethrins
present in the co-formulated pyriproxyfen products may have contributed to the adverse effects
reported in people and animals. The labels of Canadian pyriproxfen spot-on products reported in
incidents have protective measures (in other words, use of rubber gloves), as well as
precautionary statements, to minimize the likelihood of exposure in people. Domestic class
Canadian pyriproxyfen products registered for use in indoor areas are co-formulated with the
synthetic pyrethroids, d-phenothrin or tetramethrin. A trend analysis conducted on incidents
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involving synthetic pyrethroid products (2011 Report on Pesticide Incidents), including those
containing d-phenothrin and tetramethrin, identified concerns pertaining to inhalation and dermal
exposure of people and animals following or during the treatment of indoor areas. Label
amendments as outlined in PRO2018-04, Structural Pest Control Products: Label Updates are
therefore proposed to minimize the likelihood of human or animal exposure to pyriproxyfen
products co-formulated with synthetic pyrethroids.
4.0 Environmental Assessment
4.1 Fate and Behaviour in the Environment
Pyriproxyfen is sparingly soluble in water and is hydrolytically stable. Pyriproxyfen is not
expected to volatilize from dry or moist surfaces and, based on an adsorption/desorption study, is
immobile in soil. Pyriproxyfen is non-persistent in aerobic soil under laboratory and field
conditions. Biotransformation is the principal route of dissipation in soil. No major
transformation products are formed. Considering its immobility and non-persistence in soil and
its low water solubility, pyriproxyfen is not expected to leach into groundwater. Pyriproxyfen is
also non-persistent in aerobic water, but was shown to be persistent under anaerobic water
conditions. Pyriproxyfen is not expected to bioaccumulate in organisms.
4.2 Environmental Risk Characterization
The environmental risk assessment integrates the environmental exposure and ecotoxicology
information to estimate the potential for adverse effects on non-target species. This integration is
achieved by comparing exposure concentrations with concentrations at which adverse effects
occur. For greenhouse uses of pyriproxyfen, potential exposure was assessed for beneficial
arthropods and pollinators (typically those used inside greenhouses for production purposes) and
aquatic organisms (potential for exposure of adjacent aquatic habitats to discharge of process
waters from the greenhouse), and a qualitative risk assessment was considered.
4.2.1 Risks to Terrestrial Organisms
Based on the current use pattern (indoor use), minimal exposure to earthworms, birds, wild
mammals, and non-target terrestrial vascular plants is expected. Pyriproxyfen is an insect growth
regulator and effects on beneficial terrestrial invertebrates (bees, predatory and parasitic
arthropods) are expected. For greenhouse uses, a label statement to inform users of potential risks
to beneficial non-target invertebrates is already present on the label. No additional risk reduction
measures are proposed.
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4.2.2 Risks to Aquatic Organisms
Pyriproxyfen is highly toxic to freshwater invertebrates, freshwater fish, estuarine/marine fish,
and is very highly toxic to estuarine/marine invertebrates. Based on the current indoor use
pattern, direct exposure of pyriproxyfen to aquatic organisms is not expected. However, the
potential for indirect exposure to the discharge of greenhouse process water was considered.
Therefore, to minimize the potential exposure of aquatic organisms from the discharge of
greenhouse process water, the current label for the end-use product includes use directions
prohibiting the discharge of greenhouse process water.
In conclusion, the potential risks to non-target terrestrial and aquatic organisms from
pyriproxyfen are considered to be acceptable when the associated end-use products are used
according to the label directions. However, for consistency and to meet current labelling
standards, environmental precaution/disposal statements are proposed to be updated. For
additional details on the environmental assessment of pyriproxyfen, please refer to Proposed
Regulatory Decision Document PRDD2006-04, Pyriproxyfen and Registration Decision
RD2007-03, Pyriproxyfen.
4.2.3 Environmental Incident Reports
As of 19 March 2019, one environment incident involving pyriproxyfen has been submitted to
the PMRA database. A queen bee mortality incident was received by the PMRA in 2018
associated with a pet treatment product which contains three active ingredients (including
pyriproxyfen). A causality assessment concluded that exposure to pyriproxyfen was unlikely to
have contributed to the mortality observed.
The United States EIIS database was also searched for environment incidents in the United States
(data as of October 2015). There were two incidents involving honey bees. One incident was
assigned the certainty index of ‘possible’ while the other was considered as ‘unlikely’. In the
incident considered as possible, the reported product use site was an almond orchard where 2000
bee hives were impacted. No other details were available. These incidents occurred at outdoor
sites, which are not relevant to currently registered uses in Canada.
No additional mitigation measures are recommended based on the review of environmental
incident reports.
5.0 Value Assessment
Pyriproxyfen is a valuable tool for the management of whiteflies, an economically important pest
in greenhouse vegetable and ornamental production. It is mainly used at the end of a production
cycle, to reduce whitefly populations before the next production cycle. For greenhouse
vegetables, it is generally not applied when the fruit are present, but applied when the harvest is
complete, and the vegetative part of the plant is still present. Since whitefly feeding can adversely
affect the appearance and hence marketability of vegetables and ornamentals, maintaining high
quality and visual appeal is critical to these sectors.
Proposed Re-evaluation Decision - PRVD2019-10
Page 25
Pyriproxyfen is a valuable tool for the control of fleas in indoor, non-food areas of structures.
Pyriproxyfen is also co-formulated with other insecticides to broaden the pest spectrum,
including control of ticks in structures, on furniture and carpets.
Pyriproxyfen contributes to the management of companion animal pests (for example, fleas,
ticks, lice and mosquitoes) due to its long residual activity (5 months).
6.0 Pest Control Product Policy Considerations
6.1 Assessment of the Active Ingredient under the Toxic Substances Management Policy
The Toxic Substances Management Policy (TSMP) is a federal government policy developed to
provide direction on the management of substances of concern that are released into the
environment. The TSMP calls for the virtual elimination of Track 1 substances, in other words,
those that meet all four criteria outlined in the policy: persistent (in air, soil, water and/or
sediment), bio-accumulative, primarily a result of human activity and toxic as defined by the
Canadian Environmental Protection Act. The Pest Control Products Act requires that the TSMP
be given effect in evaluating the risks of a product.
During the review process, pyriproxyfen and its transformation products were assessed in
accordance with the PMRA Regulatory Directive DIR99-03,3 and evaluated against the Track 1
criteria. The PMRA has reached the conclusion that pyriproxyfen and its transformation products
do not meet all of the TSMP Track 1 criteria.
6.2 Formulants and Contaminants of Health or Environmental Concern
During the review process, contaminants in the active ingredient as well as formulants and
contaminants in the end-use products are compared against Parts 1 and 3 of the List of Pest
Control Product Formulants and Contaminants of Health or Environmental Concern.4 The list is
used as described in the PMRA Notice of Intent NOI2005-015 and is based on existing policies
and regulations, including the Toxic Substances Management Policy and Formulants Policy,6 and
taking into consideration the Ozone-depleting Substance Regulations, 1998, of the Canadian
Environmental Protection Act (substances designated under the Montreal Protocol).
The PMRA has reached the conclusion that pyriproxyfen and its end-use products do not contain
any formulants or contaminants identified in the List of Pest Control Product Formulants and
Contaminants of Health or Environmental Concern.
3 DIR99-03, The Pest Management Regulatory Agency’s Strategy for Implementing the Toxic Substances
Management Policy
4 SI/2005-114, last amended on 25 June 2008. See Justice Laws website, Consolidated Regulations, List of
Pest Control Product Formulants and Contaminants of Health or Environmental Concern
5 PMRA's Notice of Intent NOI2005-01, List of Pest Control Product Formulants and Contaminants of
Health or Environmental Concern under the New Pest Control Products Act.
6 DIR2006-02, Formulants Policy and Implementation Guidance Document.
Proposed Re-evaluation Decision - PRVD2019-10
Page 26
The use of formulants in registered pest control products is assessed on an ongoing basis through
the PMRA formulant initiatives and Regulatory Directive DIR2006-02.
7.0 Conclusion of Science Evaluation
Pyriproxyfen is an insect growth regulator belonging to juvenile hormone mimics. Pyriproxyfen
is a valuable tool in the management of white flies in greenhouse vegetable and ornamental
production, flea control in indoor, non-food areas of structures and management of fleas on cats
and dogs.
With respect to human health, the health risks associated with the use of pyriproxyfen and
associated end-use products are acceptable when these products are used according to the
proposed revised label directions (Appendix VI).
When used according to the proposed label directions, potential risks to the environment from
the use of pyriproxyfen and associated end-use products have been shown to be acceptable.
List of Abbreviations
Proposed Re-evaluation Decision - PRVD2019-10
Page 27
List of Abbreviations
abs absolute
AD administered dose
ADI acceptable daily intake
ALK alkaline phosphatase
ALT alanine aminotransferase
AR androgen receptor
ARfD acute reference dose
AST aspartate aminotransferase
BUN blood urea nitrogen
bw body weight
bwg bodyweight gain
CAF composite assessment factor
CYP cytochrome P450 enzyme(s)
DEHP di-2-ethylhexyl phthalate
DNA deoxyribonucleic acid
EC10 effective concentration to produce a 10% response
ER estrogen receptor
F0 parental generation
F1 first generation
F2 second generation
fc food consumption
Hct hematocrit
Hgb hemoglobin
hr(s) hour(s)
GD gestation day
kg kilogram(s)
L litre(s)
LABC levator ani-bulbocavernosus muscle complex
LC50 lethal concentration to 50%
LD lactation day
LDH lactate dehydrogenase
LD50 lethal dose to 50%
LOAEC lowest observed adverse effect concentration
LOAEL lowest observed adverse effect level
M molar
MAS maximum average score for 24, 48 and 72 hours
MCH mean cell hemoglobin
MCV mean cell volume
mg milligram(s)
MIS maximum irritation score
mL millilitre(s)
MOE margin of exposure
MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
NOAEC no observed adverse effect concentration
List of Abbreviations
Proposed Re-evaluation Decision - PRVD2019-10
Page 28
NOAEL no observed adverse effect level
NRI50 neutral red incorporation to 50%
PCPA Pest Control Products Act
PMRA Pest Management Regulatory Agency
PND postnatal day
ppm parts per million
RBC red blood cell
rel relative
S9 metabolic activation
sRBC sheep red blood cells
T3 triiodothyronine
T4 thyroxine
TSH thyroid stimulating hormone
UGT uridine 5'-diphospho-glucuronosyltransferase
μM micromolar
wt weight
wc water consumption
wk(s) week(s)
Appendix I
Proposed Re-evaluation Decision - PRVD2019-10
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Appendix I Lists of Pyriproxyfen Products and Uses
Table 1 Registered Pyriproxyfen Products in Canada as of 1 May 2019 excluding discontinued products or products with a
submission for discontinuation
Registration
Number
Marketing Class
Registrant
Product Name
Formulation Type
Active Ingredient
25105
Technical Grade Active
Ingredient
Sumitomo Chemical
Company Ltd.
SUMILARV TECHNICAL
GRADE
Solid
Pyriproxyfen 98.7%
25489
Manufacturing
Concentrate
McLaughlin Gormley King
Company
NYLAR 50%
CONCENTRATE
Solution
Pyriproxyfen 50%
27545
Rolf C. HAGEN Inc.
PERMETHRIN NYLAR
SQUEEZE ON
MANUFACTURING
BLEND
Solution
Pyriproxyfen 1.9%
Permethrin 45%
27705
ETOFENPROX NYLAR
SQUEEZE ON
MANUFACTURING
BLEND
Pyriproxyfen 2.2%
Etofenprox 55%
25490
Commercial
McLaughlin Gormley King
Company
NYGUARD IGR
CONCENTRATE
Emulsifiable
Concentrate
Pyriproxyfen 10%
28414
VALENT Canada Inc.
DISTANCE
Emulsifiable
Concentrate
Pyriproxyfen 103 g/L
27581
Domestic
BAYER Inc.
ADVANTAGE II SMALL
DOG
Solution
Pyriproxyfen 0.46%
Imidacloprid 9.1%
27582
ADVANTAGE II LARGE
DOG
27583
ADVANTAGE II MEDIUM
DOG
27584
ADVANTAGE II EXTRA
LARGE DOG
27585
ADVANTAGE II SMALL
CAT
27586
ADVANTAGE II LARGE
CAT
29777
K9 ADVANTIX II SMALL
DOG
Pyriproxyfen 0.44%
Permethrin 44%
Imidacloprid 8.8%
29778
K9 ADVANTIX II
Appendix I
Proposed Re-evaluation Decision - PRVD2019-10
Page 30
Registration
Number
Marketing Class
Registrant
Product Name
Formulation Type
Active Ingredient
MEDIUM DOG
29779
K9 ADVANTIX II EXTRA
LARGE DOG
29780
K9 ADVANTIX II LARGE
DOG
31517
ADVANTAGE II KITTENS
Pyriproxyfen 0.46%
Imidacloprid 9.1%
31119
Domestic
HARTZ Canada Inc.
HARTZ ULTRAGUARD
PLUS FLEA & TICK
HOME SPRAY
Solution
Pyriproxyfen 0.015%
D-phenothrin 0.40%
Piperonyl butoxide
1%
31749
HARTZ ULTRAGUARD
PRO FLEA & TICK
SHAMPOO FOR DOGS
Emulsifiable
Concentrate
Pyriproxyfen 0.075%
D-phenothrin 0.270%
S-methoprene 0.04%
25491
Domestic
McLaughlin Gormley King
Company
NYLAR PRESSURIZED
SPRAY 2618
Pressurized product
Pyriproxyfen 0.015%
D-phenothrin 0.30%
Tetramethrin 0.40%
31941
Domestic
Neogen Corporation
PROZAP PET GUARD IGR
FLEA SPRAY
Pressurized product
Pyriproxyfen 0.015%
D-phenothrin 0.30%
Tetramethrin 0.40%
26179
Domestic
Premier Tech Ltd.
C-I-L FLEA KILLER
SURFACE SPRAY
Pressurized product
Pyriproxyfen 0.015%
D-phenothrin 0.300%
Tetramethrin 0.400%
26502
Domestic
Rolf C. HAGEN Inc.
SERGEANT'S PRETECT
HOUSEHOLD FLEA
SPRAY
Pressurized product
Pyriproxyfen 0.015%
D-phenothrin 0.3%
Tetramethrin 0.4%
28113
SERGEANT'S PRETECT
SQUEEZE-ON FLEA, TICK
& MOSQUITO CONTROL
FOR DOGS (UP TO 15 KG)
Liquid
Pyriproxyfen 1.9%
Permethrin 45%
28280
SEARGEANT'S PRETECT
SQUEEZE-ON FLEA, TICK
& MOSQUITO CONTROL
FOR DOGS (OVER 30 KG)
Solution
28281
SERGEANTS PRETECT
SQUEEZE-ON FLEA, TICK
&MOSQUITO CONTROL
FOR DOGS (15-30 KG)
Appendix I
Proposed Re-evaluation Decision - PRVD2019-10
Page 31
Registration
Number
Marketing Class
Registrant
Product Name
Formulation Type
Active Ingredient
28610
SERGEANT'S PRE TECT
SQUEEZE-ON FLEA
CONTROL FOR CATS
AND KITTENS
Pyriproxyfen 2.2%
31608
SENTRY FLEA SQUEEZE-
ON FOR CATS AND
KITTENS
31609
SENTRY FLEA, TICK &
MOSQUITO SQUEEZE-ON
FOR DOGS (15 TO 30 KG)
Pyriproxyfen 1.9%
Permethrin 45%
31610
SENTRY FLEA, TICK &
MOSQUITO SQUEEZE-ON
FOR DOGS (OVER 30 KG)
31611
SENTRY FLEA, TICK &
MOSQUITO SQUEEZE-ON
FOR DOGS (UP TO 15 KG)
31647
SENTRY HOUSEHOLD
FLEA SPRAY
Pressurized product
Pyriproxyfen 0.015%
D-phenothrin 0.30%
Tetramethrin 0.40%
32546
SERGEANT'S GUARDIAN
FLEA, TICK & MOSQUITO
CONTROL FOR DOGS (15
TO 30 KG)
Solution
Pyriproxyfen 1.9%
Permethrin 45.0%
32547
SERGEANT'S GUARDIAN
FLEA CONTROL FOR
CATS & KITTENS
Pyriproxyfen 2.2%
32548
SERGEANT'S GUARDIAN
FLEA, TICK & MOSQUITO
CONTROL FOR DOGS
(OVER 30 KG)
Pyriproxyfen 1.9%
Permethrin 45.0%
32549
SERGEANT'S GUARDIAN
FLEA, TICK & MOSQUITO
CONTROL FOR DOGS (UP
TO 15 KG)
Liquid
Pyriproxyfen 1.9%
Permethrin 45.0%
Appendix I
Proposed Re-evaluation Decision - PRVD2019-10
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Table 2 Registered Commercial and Restricted Class Uses of Pyriproxyfen as of 1 May 2019 excluding discontinued products
or products with a submission for discontinuation
Site
Pest(s)
Formulation
type
Application Method
and Equipment
Maximum
Single
Application
Rate
Maximum
Cumulative
Application Rate
per Year
Maximum
Number of
Applications
per year
Minimum
Interval
Between
Applications
(Days)
USC 5 Greenhouse Food Crops
Greenhouse
cucumbers
Greenhouse eggplant
Greenhouse peppers
Greenhouse tomatoes
Silverleaf whitefly,
sweet potato
whitefly,
greenhouse whitefly
Emulsifiable
Concentrate
Ground application
foliar spray
4.64 g a.i./100L
18.56 g a.i ./100L
2 per crop
Maximum 2
applications
per six months
(4/year)
14
USC 6 Greenhouse Non-food Crops
Greenhouse
ornamentals
Silverleaf whitefly,
sweet potato
whitefly,
greenhouse whitefly
Emulsifiable
Concentrate
Ground application
foliar spray
4.64 g a.i./100L
18.56 g a.i ./100L
2 per crop
Maximum 2
applications
per six months
(4/year)
14
USC 20 - Structural
Indoor
(Homes, apartment
buildings, Office
Buildings,
Automobiles, Buses,
Boats,
Ship Cabins and
Holds, Trucks,
Boxcars and Non-
Food Areas of Hotels
and Motels)
Fleas
(inhibits growth of
larvae)
Emulsifiable
Concentrate
Broadcast
application, spot and
crack and crevice
application.
Any low pressure
sprayer typically used
for indoor
applications
0.48 g
a.i./100m2
0.96 g a.i./100m2
2
150
Appendix I
Proposed Re-evaluation Decision - PRVD2019-10
Page 33
Table 3 Registered Domestic Class Uses of Pyriproxyfen as of 1 May 2019, excluding discontinued products or products with
a submission for discontinuation1
Site
Pest(s)
Formulations
Application Method and
Equipment
Maximum
Single
Application
Rate
(g a.i./ha)
Maximum
Cumulative
Application Rate
per Year
Maximum
Number of
Applications
per year1
Minimum
Interval
Between
Applications1
(Days)
USC 20 Structural
Indoors
(Homes,
garages, attics
and
apartments.)
Fleas
(larvae) and
ticks
Solution
Fine spray applied
uniformly to carpets, rugs,
pet bedding and all
surfaces of upholstered
furniture where pests are
found.
6.2 mg a.i./m2
12.4 mg a.i./m2
[2]
[182]
Indoors
(Residential and
Commercial
uses)
Fleas
(Adults and
Pre-adult)
Pressurized
Product
Spot and crack-and-
crevice application only
Apply only to localized
areas of flea infestation,
such as pet bedding
6.56 mg
a.i./m2
13.12 mg a.i./m2
[2]
[180]
USC 24 Companion Animals
Cats
(2.3 kg or less)
(Do not use on
kittens under 8
weeks of age)
Fleas
(larvae,
adult, egg)
Solution
Place the tip of the
applicator tube on the skin
and squeeze the tube to
completely empty the
contents directly on the
skin as a single spot.
1.16 mg
a.i./application
13.9 mg a.i.
12
30
Cats
(2.34 kg)
(Do not use on
kittens under 8
weeks of age)
2.01 mg
a.i./application
24.12 mg a.i.
Cats
(over 4 kg)
(Do not use on
4.03 mg
a.i./application
48.4 mg a.i.
Appendix I
Proposed Re-evaluation Decision - PRVD2019-10
Page 34
Site
Pest(s)
Formulations
Application Method and
Equipment
Maximum
Single
Application
Rate
(g a.i./ha)
Maximum
Cumulative
Application Rate
per Year
Maximum
Number of
Applications
per year1
Minimum
Interval
Between
Applications1
(Days)
kittens under 8
weeks of age)
Cats
(4 kg or less)
(Do not use on
kitten under 12
weeks of age)
Fleas (eggs)
Solution
Place the tip of the
applicator tube on the skin
and squeeze the tube to
completely empty the
contents directly on the
skin as a single spot.
34.3 mg
a.i./application
137.2 mg a.i.
4
90
Cats
(over 4 kg)
(Do not use on
kitten under 12
weeks of age)
164.6 mg a.i.
4.8
75
Dogs
(up to 4.5 kg)
(Do not use on
puppies under 7
weeks of age)
Fleas
(larvae,
adult, egg)
and
lice
Solution
Place the tip of the
applicator tube on the skin
and squeeze the tube to
completely empty the
contents directly on the
skin as a single spot.
1.84 mg
a.i./application
22.08 mg a.i.
12
30
Dogs
(4.6 –11 kg)
(Do not use on
puppies under 7
weeks of age)
5 mg
a.i./application
60 mg a.i.
Dogs
(1125 kg)
(Do not use on
puppies under 7
weeks of age)
12.6 mg
a.i./application
151 mg a.i.
Dogs
(over 25 kg)
20.1 mg
a.i./application
241.2 mg a.i.
Appendix I
Proposed Re-evaluation Decision - PRVD2019-10
Page 35
Site
Pest(s)
Formulations
Application Method and
Equipment
Maximum
Single
Application
Rate
(g a.i./ha)
Maximum
Cumulative
Application Rate
per Year
Maximum
Number of
Applications
per year1
Minimum
Interval
Between
Applications1
(Days)
(Do not use on
puppies under 7
weeks of age)
Dogs
(4.5 kg or less)
(Do not use on
puppies under 8
weeks of age)
Fleas
(larvae,
adult, egg),
ticks
(adults),
mosquitos
(adults) and
lice (adults)
Solution
Place the tip of the
applicator tube on the skin
and squeeze the tube to
completely empty the
contents directly on the
skin as a single spot.
2 mg
a.i./application
24 mg a.i.
12
30
Dogs
(4.6 –11 kg)
(Do not use on
puppies under 8
weeks of age)
5 mg
a.i./application
60 mg a.i.
Dogs
(1125 kg)
(Do not use on
puppies under 8
weeks of age)
12.5 mg
a.i./application
150 mg a.i.
Dogs
(over 25 kg)
(Do not use on
puppies under 8
weeks of age)
20.1 mg
a.i./application
241.2 mg a.i.
Dogs
(Do not use on
puppies under 6
months of age
and nursing
animals)
Fleas
(larvae, egg),
ticks (adults)
Emulsifiable
Concentrate
Place the tip of the
applicator tube on the skin
and squeeze the tube to
completely empty the
contents directly on the
skin as a single spot.
1.7 mg a.i./kg
body
weight./applic
ation
88.4 mg a.i./kg
body weight
52
7
Appendix I
Proposed Re-evaluation Decision - PRVD2019-10
Page 36
Site
Pest(s)
Formulations
Application Method and
Equipment
Maximum
Single
Application
Rate
(g a.i./ha)
Maximum
Cumulative
Application Rate
per Year
Maximum
Number of
Applications
per year1
Minimum
Interval
Between
Applications1
(Days)
Dogs
(up to 15 kg)
(Do not use on
puppies under 3
months)
Fleas,
mosquitoes,
brown dog
ticks,
blacklegged
(deer) ticks
and
American
dog ticks.
Inhibits flea
egg
development
.
Solution
Place the tip of the
applicator tube on the skin
and squeeze the tube to
completely empty the
contents directly on the
skin as a single spot.
28.5 mg
a.i./application
342 mg a.i.
12
30
Dogs
(1530 kg)
(Do not use on
puppies under 3
months)
57 mg
a.i./application
684 mg a.i.
Dogs
(over 30 kg)
(Do not use on
puppies under 3
months)
85.5 mg
a.i./application
1026 mg a.i.
Dogs
(up to 15 kg)
(Do not use on
puppies under 3
months of age
and nursing
animals)
32.5 mg
a.i./application
390 mg a.i.
Dogs
(1530 kg)
(Do not use on
puppies under 3
months of age
and nursing
animals)
65 mg
a.i./application
780 mg a.i.
Appendix I
Proposed Re-evaluation Decision - PRVD2019-10
Page 37
Site
Pest(s)
Formulations
Application Method and
Equipment
Maximum
Single
Application
Rate
(g a.i./ha)
Maximum
Cumulative
Application Rate
per Year
Maximum
Number of
Applications
per year1
Minimum
Interval
Between
Applications1
(Days)
Dogs
(over 30 kg)
(Do not use on
puppies under 3
months of age
and nursing
animals)
97.6 mg
a.i./application
1171.2 mg a.i.
1 Information in Square [ ] brackets is based upon consultation with the registrant
Appendix II
Proposed Re-evaluation Decision - PRVD2019-10
Page 38
Appendix II Toxicological Information for Health Risk Assessment
Table 1 Chemical Names of Pyriproxyfen and Select Metabolites
Compound
Identifier
Chemical Name
pyriproxyfen
4-phenoxyphenyl (RS)-2-(2-pyridyloxy) propyl ether
4'-OH -pyr
4-(4-hydroxyphenoxy)phenyl (RS)-2-(2-pyridyloxy)propyl ether
2'-OH-pyr
4-(2-hydroxyphenoxy)phenyl (RS)-2-(2-pyridyloxy)propyl ether
5",4'-OH-pyr
4-(4'-hydroxyphenoxy)phenyl (RS)-2-(5-hydroxypyridyl-2-oxy)propyl
ether
5"-OH-pyr
(RS)-5-hydroxy-2-{1-methyl-2-(4-phenoxyphenoxy)}ethoxy pyridine
DPH-pyr
4-hydroxyphenyl (RS)-2-(2-pyridyloxy)propyl ether
PYPA
(RS)-2-(2-pyridyloxy)propanol
PYPAC
(RS)-2-(2-pyridyloxy)propionic acid
2-OH-py
2-hydroxypyridine
POPA
4-phenoxyphenyl (RS)-2-hydroxypropyl ether
4'-OH-POPA
4-(4-hydroxyphenoxy)phenyl (RS)-2-hydroxypropyl ether
4'-OH-POP
4,4'-oxydiphenol
2,5-OH-py
2,5-hydroxypyridine
Table 2 Summary of Toxicology Studies for Pyriproxyfen
NOTE: Effects noted below are known or assumed to occur in both sexes unless otherwise noted;
in such cases, sex-specific effects are separated by semi-colons. Effects on organ weights are
known or assumed to reflect changes in absolute weight and relative (to bodyweight) weight
unless otherwise noted.
Study Type/
Animal/PMRA #
Study Results
Toxicokinetic Studies
Sprague Dawley Rat
PMRA# 1143941, 1143949,
1159016
Sprague Dawley rats were given a single oral dose of 2 mg/kg bw or 1000
mg/kg bw [phenyl-14C] pyriproxyfen, or a single oral dose of 2 mg/kg bw
[phenyl-14C] pyriproxyfen following oral administration of 2 mg/kg bw/day
unlabelled pyriproxyfen over two weeks; excreta were collected over 7 days.
Additionally, Sprague Dawley rats were given a single oral dose of 2 mg/kg
bw [phenyl-14C] pyriproxyfen and tissues were sampled at 2, 4, 8, 12, 24, 48
and 72 hrs.
Absorption: Based on urine concentration data, pyriproxyfen was not well-
absorbed. Peak blood levels following a single low dose were noted at 2 hrs
(♂) or 224 hrs (♀); ♂ showed 4-fold higher 14C concentrations in blood
than ♀ until 24 hrs after administration.
Distribution: In ♂ and ♀ rats, the maximum total tissue 14C residue
concentrations were 7.3% and 5.2% of the AD respectively, 8 hrs following
a single oral low dose. Maximum tissue concentrations were highest in liver,
blood (♂ only), kidneys and adipose tissues. The
14
C levels in adipose tissue
Appendix II
Proposed Re-evaluation Decision - PRVD2019-10
Page 39
Study Type/
Animal/PMRA #
Study Results
were the highest tissue levels after 7 days. All other non-adipose tissues
contained 14C residue concentrations of ≤0.001, ≤0.6, and ≤0.003 ppm for
the low, high, and repeated-dose groups, respectively. There were no
significant sex or dose-related differences in tissue distribution.
Sprague Dawley Rat
PMRA# 2704562
PMRA #2704562 Sprague Dawley rats were administered [pyridyl-2,6-
14C] pyriproxyfen as single oral doses of 2.0 mg/kg bw or 1000 mg/kg bw;
urine and feces were collected for 7 days. Additional ♂ rats were orally
dosed with [phenyl-14C] pyriproxyfen, from which urine and feces were
collected for 2 days.
Absorption: Based on urine concentration data, pyriproxyfen was not well-
absorbed.
Distribution: Tissues accumulated very little radioactivity; fat contained the
greatest amount at 0.024 - 0.042% of the AD 7 days after dosing; no dose or
sex difference was noted.
Excretion: Pyriproxyfen was rapidly eliminated with >85% of the AD
eliminated in the first 48 hrs, primarily in the feces. After 7 days, >84% of
the AD was in the feces and up to 12% was in the urine. Small amounts of
radioactivity were detected in expired air (≤0.5% of the AD). There were no
effects of sex, dose or label position on elimination.
Metabolism: Metabolite analyses were conducted using urine and feces
collected during the first 48 hrs after dosing; The major fecal metabolite was
4'-OH-pyr, comprising 2347% of the AD. Unchanged pyriproxyfen in feces
accounted for 2135% of the AD. Minor fecal metabolites included 2'-OH-,
5''-OH-, and 5'', 4'-OH-pyr. Sulfate conjugates of 4'-OH and 5'', 4'-OH-pyr
and a glucuronide conjugate of the 4'-OH-pyr were detected. 5'', 4'-OH-pyr
was detected in low-dose ♂ at 7.2% of the AD; all other minor fecal
metabolites and conjugates were detected at ≤4% in both sexes at each dose.
DPH-pyr, a product of cleavage of the terminal phenyl ring was present in
feces at <2% of the AD. Unchanged pyriproxyfen and 4'-OH-pyr were
detected in minor amounts in the urine of high-dose rats (13% and 16%
respectively), but were absent in urine of the low-dose rats. PYPAC, a
pyridyl metabolite from cleavage of both phenyl rings was present in urine at
1–5%, but was not detected in feces. Minor amounts of the sulfate
conjugates were detected in urine.
The major pathway of pyriproxyfen metabolism in rats involves
hydroxylation at the 4'-position of the terminal phenyl ring. Minor pathways
include hydroxylation at the 2'-position of the terminal phenyl ring and at the
5''-pyridyl position, dephenylation, cleavage of ether linkages, and formation
of glucuronide and sulfate conjugates. There were no significant effects of
sex or dose on the metabolic pattern of pyriproxyfen.
Acute Toxicity Studies
Acute Oral
Sprague Dawley Rat
PMRA #1143889, 1159046
Low toxicity
LD50 > 5000 mg/kg bw (corn oil)
No deaths. Clinical signs (↓ spontaneous activity, soft faeces, diarrhea, ↓
bwg at ≥ 2500 mg/kg bw) resolved within 2 days.
Acute Dermal
Sprague Dawley Rat
Low toxicity
LD50 > 2000 mg/kg bw (corn oil)
Appendix II
Proposed Re-evaluation Decision - PRVD2019-10
Page 40
Study Type/
Animal/PMRA #
Study Results
PMRA #1143893, 1159057
No deaths or clinical signs of toxicity.
Acute Inhalation (4 hr,
whole body)
Sprague Dawley Rat
PMRA #1143894, 1159068,
2704564
Slight toxicity
LC50 >1.3 mg/L (corn oil)
1.3 mg/L: Transient clinical signs of toxicity, salivation (2/5 ♂ and 1/5 ♀);
urinary incontinence (♀).
Primary Skin Irritation
NZW Rabbit
PMRA #1143896
Non-irritating.
MAS = 4.5 (24, 48 and 72 hrs)
Primary Eye Irritation
NZW Rabbit
PMRA #1143896
Minimally irritating.
MIS = 4.7 (at 1 hr)
Skin Sensitization
(Maximization method)
Hartley Guinea Pig
PMRA #1143897
Not a dermal sensitizer.
Short-Term Toxicity Studies
21-Day Dermal
Sprague Dawley Rat
PMRA #1164979
NOAEL = 1000 mg/kg bw/day (corn oil)
No compound-related changes were noted.
28-Day Inhalation
(whole-body)
Sprague Dawley Rat
PMRA #1143883
NOAEC = 0.482 mg/L (84 mg/kg bw/day)(♂); 1 mg/L (174 mg/kg
bw/day)(♀)
1.00 mg/L (174 mg/kg bw/day): salivation during initial exposures; bw, ↑
LDH, ↓ abs lung wt (♂); ↑ wc (♀).
90-Day Oral
(dietary)
CDBR Rat
PMRA #1143899, 1159075
NOAEL = 400 ppm (24/28 mg/kg bw/day in ♂/♀)
≥2000 ppm (118/141 mg/kg bw/day): cytoplasmic change consisting of ↑ in
cytoplasmic content, ↓nucleus/cytoplasm ratio and ↓ sinusoidal space; ↓
RBC, ↓ Hgb, Hct, ↑ cholesterol, ↑ phospholipid, rel liver wt (♂); ↓MCV
(♀).
≥5000 ppm (309/356 mg/kg bw/day): bw, ↑ liver wt; rel kidney wt (♂);
↓ RBC, ↓ Hgb, ↓Hct, ↑ cholesterol (♀).
10 000 ppm (642/784 mg/kg bw/day): total protein, ↑ albumin; ↑
phospholipid, ↑ rel kidney wt (♀).
90-Day Oral
(dietary)
NOAEL = 1000 ppm (149/197 mg/kg bw/day in ♂/♀)
Appendix II
Proposed Re-evaluation Decision - PRVD2019-10
Page 41
Study Type/
Animal/PMRA #
Study Results
CD-1 Mouse
PMRA #1164978
≥5000 ppm (838/964 mg/kg bw/day): hunched posture, few or no feces,
↓Hgb, ↓ Hct, ↑ platelets, ↑ wc, ↑ BUN, ↑ rel liver wt, renal effects (tubular
nephrosis, dilation of renal tubules and pelvis, focal mineralization); ↑
mortality, ↓ bw, ↓ bwg, ↑ rel adrenal gland wt, ↓ MCV, MCH, ↑ AST,
ALT, thymic lymphoid depletion, bone marrow myeloid hyperplasia, ↑
spleen pigmentation (♂); thin appearance, ↓ RBC, ↑ cholesterol, ↑
phospholipids, ↑ abs liver wt (♀).
10,000 ppm (2035/2345 mg/kg bw/day): myeloid hyperplasia of bone
marrow, cardiomyopathy, thymic atrophy; ↓ RBC, mortality, ↓ bw, thymic
lymphoid depletion, ↑ spleen pigmentation, extra medullary hematopoiesis
(♀).
90-Day Oral
(capsule)
Beagle Dog
PMRA #1143898
NOAEL = 100 mg/kg bw/day (♀); 300 mg/kg bw/day (♂)
300 mg/kg bw/day: ↑ liver wt; hepatocellular enlargement, ↑ cholesterol, ↑
phospholipid (♀).
1000 mg/kg bw/day: hepatic cytoplasmic changes (eosinophilic bodies, ↑ in
smooth endoplasmic reticulum proliferation, dilation of endoplasmic
reticulum); hepatocellular enlargement (♂).
52-Week Oral
(capsule)
Beagle Dog
PMRA #1143882, 2704560,
1159076
NOAEL = 30 mg/kg bw/day (♂); 100 mg/kg bw/day (♀)
≥30 mg/kg bw/day: rel liver wt (♂).
≥100 mg/kg bw/day: bwg, ↑ cholesterol, ↑ liver wt; bw, ↑ triglycerides, ↑
ALK in one animal (♂)
≥300 mg/kg bw/day: ALK; thin appearance, ↑ platelets, submucosal
fibrosis of the gall bladder (♂); ↓ bw, ↑ triglycerides, ↑ rel kidney wt, ↑
thyroid wt (♀).
1000 mg/kg bw/day: salivation, diarrhea, emesis, ↑ ALT, centriacinar
fibrosis, bile duct hyperplasia, active chronic inflammatory infiltrate,
submucosal edema of the gall bladder; 2 mortalities (sacrificed due to
toxicity), bw loss, ↑ prothrombin time, ↑ AST, ↑ bilirubin, ↑ urinary volume,
↓ pH, nodular hyperplasia, (♂); ↑ platelets, submucosal fibrosis of the gall
bladder (♀).
52-Week Oral
(capsule)
Beagle Dog
PMRA #2704560
NOAEL = 10 mg/kg bw/day
≥3 mg/kg bw/day: slight ↑ platelets (♂).
10 mg/kg bw/day: slight ↑ platelets (♀).
Chronic Toxicity/Oncogenicity Studies
78-Week Oncogenicity
(dietary)
CD-1 Mouse
PMRA #1143912, 1143930,
1159013, 1169747, 2704561
NOAEL = 120 ppm (16 mg/kg bw/day) (♂); 600 ppm (107 mg/kg
bw/day)(♀)
≥120 ppm (16/21 mg/kg bw/day: hunched posture.
≥600 ppm (79/107 mg/kg bw/day): survival after week 64, ↑ severity of
amyloidosis in kidneys, thyroid, parathyroid and stomach of decedents (♂).
3000 ppm (413/530 mg/kg bw/day): ↓ bw, granular/pitted/rough kidneys,
Appendix II
Proposed Re-evaluation Decision - PRVD2019-10
Page 42
Study Type/
Animal/PMRA #
Study Results
accelerated development and severity of amyloidosis (multi-tissue), ↑
incidence of chronic progressive nephropathy, ↑ incidence of mineralized
renal tubules; ↓ survival after week 60, ↓ motor activity, ↓ bwg up to wk 24,
↓ abs kidney wt at termination (♂); ↓ survival after wk 64, ↓ bwg,
erythrocyte changes at wk 52 (↓ Hgb, slight ↓ RBC, slight ↓ Hct, ↑
polychromatic RBC), ↑ liver wt at wk 52, ↑ abs spleen wt at wk 52 (♀).
No evidence of carcinogenicity.
2-Year Chronic
Toxicity/Oncogenicity
(dietary)
Sprague Dawley Rat
PMRA #1143884, 1143902,
1143903, 2704559,
2704558, 1159077, 1164935
NOAEL = 600 ppm (27/35 mg/kg bw/day)
≥600 ppm (27/35 mg/kg bw/day: urinary pH at wk 26 (♀)(non-adverse).
3000 ppm (138/183 mg/kg bw/day): bw, ↓bwg, ↑ phospholipid and
cholesterol at wk 26; ↑ cholesterol wks 52, 78 (♂); ↑ urinary protein at wk
26, ↑ rel liver wt at interim and terminal sacrifice (♀).
No evidence of carcinogenicity.
Developmental/Reproductive Toxicity Studies
Two-generation
Reproductive Toxicity
(dietary)
Sprague Dawley Rat
PMRA #1143904, 1143905
Parental
NOAEL = 1000 ppm (64/103 mg/kg bw/day)
≥1000 ppm (80 mg/kg bw/day): rel liver wt, ↑ rel kidney wt (F1♂).
5000 ppm (328/531 mg/kg bw/day): bw (pre-mating, F0, F1), ↓ bwg (pre-
mating, F0, F1), sporadic ↓ fc, ↑ liver wt (F1); chronic interstitial nephritis,
focal clear cells in liver (F1 ♂).
Offspring
NOAEL = 1000 ppm (103 mg/kg bw/day)
5000 ppm (531 mg/kg bw/day): ↓ pup bw PND 14 and 21 (F1 and F2).
No evidence of increased sensitivity of the young.
Reproductive
NOAEL = 5000 ppm (328/531 mg/kg bw/day)
No effect on reproductive parameters.
Reproductive/Developmental
Toxicity non-guideline
(gavage)
Sprague Dawley Rat
PMRA #2704582
Exposure from 9-weeks pre-
mating to GD 7 and
examination of fetuses at GD
21
Parental
NOAEL = 100 mg/kg bw/day
≥100 mg/kg bw/day: transient salivation immediately following dosing; ↑
wc, ↑ rel liver wt, ↑ rel kidney wt, ↑ adrenal wt (♂).
≥300 mg/kg bw/day: erythema, ↓ bwg; ↓ bw, ↑ fc, ↓ thymus wt, ↑ abs liver
wt, ↑ abs kidney wt, enlargement of the liver, dark-red colour of the liver,
pitted surface of the kidney, enlargement of the adrenals (♂); diarrhea,
swelling of the periproctal region, ↑ wc during gestation (♀).
≥500 mg/kg bw/day: diarrhea, swelling of the periproctal region,
enlargement of the kidney (♂); ↑wc during pre-mating (♀).
1000 mg/kg bw/day: lacrimation, atrophy of the thymus (♂); mortality in 2
Appendix II
Proposed Re-evaluation Decision - PRVD2019-10
Page 43
Study Type/
Animal/PMRA #
Study Results
animals, ↓ bw, ↑fc during gestation, hypoactivity, wasting (♀).
Developmental
NOAEL = 1000 mg/kg bw/day
No effects on fetal weight, sex or development.
Reproductive
NOAEL = 500 mg/kg bw/day
1000 mg/kg bw/day: number of corpora lutea per dam.
No evidence of sensitivity of the young.
Developmental Toxicity
(gavage)
Sprague Dawley Rat
PMRA #1143907, 1159015
Exposure from GD 7-17,
examination of fetuses at GD
21 and pups at 3 weeks
(general toxicity), 8 weeks
(open field test, motor co-
ordination test and learning
ability) and 11 weeks
(reproductive performance)
Maternal
NOAEL = 100 mg/kg bw/day
100 mg/kg bw/day: transient bwg.
≥300 mg/kg bw/day: bw, ↓ bwg, ↓ fc, ↑ wc, ↑ rel liver wt, ↑ rel kidney wt.
1000 mg/kg bw/day: mortality (all deaths occurring after 4-9 doses), soft
stool, erythema, swelling of the periproctal region, bw loss in first few days
of dosing, ↑ adrenal wt, ↓ thymus wt, abs spleen wt, ↓ abs heart wt, ↑ abs
kidney wt, adrenal enlargement (GD 21), thymic involution (GD 21), ↑ early
resorptions (attributable to 100% resorptions in 2 dams).
Dams that died showed hypoactivity, wasting, bloody dirtiness around the
nose, blanching of the auricle and extremities, hypothermia, kidney and liver
congestion, splenic atrophy, adrenal enlargement, thymic involution,
stomach haemorrhage or ulceration.
Developmental/Offspring
NOAEL = 100 mg/kg bw/day
≥300 mg/kg bw/day: ↑ incidence of opening of the 7th cervical vertebra
foramen transversium, ↑ total incidence of skeletal variations in 3-wk-old
pups.
1000 mg/kg bw/day: total fetal incidence of skeletal variations, ↑
incidence of renal pelvis dilatation in 3- and 8-wk-old pups, ↑ rel kidney wt
in 8-wk-old ♀ pups.
No effects on sensory function, behaviour, motor coordination or learning
ability in pups.
Reproductive
NOAEL = 1000 mg/kg bw/day
No effects on reproductive performance in pups.
No evidence of sensitivity of the young. Not teratogenic.
Reproductive/Developmental
Toxicity
(gavage)
Maternal
NOAEL = 100 mg/kg bw/day
≥300 mg/kg bw/day: diarrhea, salivation, ↓bw (GD 20-22), ↓fc (GD 19-22,
Appendix II
Proposed Re-evaluation Decision - PRVD2019-10
Page 44
Study Type/
Animal/PMRA #
Study Results
Sprague Dawley Rat
PMRA #2704580
Exposure from GD 17-
LD20, examination of pups
at PND 4 (skeletal
anomalies), 3 weeks (general
toxicity), 8 weeks (open field
test, motor co-ordination test
and learning ability) and 11
weeks (reproductive
performance)
LD21), ↑liver wt.
500 mg/kg bw/day: mortality (2 dams after 5 doses), erythema and swelling
of the periproctal region, hypoactivity, lacrimation, rough hair, hypothermia,
atrophy of the thymus, congestion of liver, atrophy of spleen and adrenals,
ulcers of the stomach.
Offspring
NOAEL = 100 mg/kg bw/day
≥300 mg/kg bw/day: pup weight (PND 0-56), ↑incidence of dilatation of
the renal pelvis, equivocal ↓viability index at PND 21.
500 mg/kg bw/day: ↓viability index at PND 4 and 21 (F1), slight delay in
vaginal opening (F1).
No effects on sensory function, behaviour, motor coordination or learning
ability in pups.
Reproductive
NOAEL = 100 mg/kg bw/day
300 mg/kg bw/day: pup birth wt (F1)
500 mg/kg bw/day: ↓ mean implantations (F1), ↑pre-implantation loss (F1),
↓livebirth index (F1), ↓litter size (F1).
No evidence of sensitivity of the young.
14-Day Toxicity
(gavage)
JW NIBS Rabbit (non-
pregnant)
PMRA #2704576
Range-finding study - supplemental
1000 mg/kg bw/day: ↓ bw, ↓ bwg, ↓ fc.
Developmental Toxicity
(gavage)
JW-NIBS Rabbit
PMRA #1143906, 1159014,
1164980
Maternal
NOAEL = 100 mg/kg bw/day
≥300 mg/kg bw/day: bwg, ↓ fc, late abortions/ premature deliveries, in
dams that aborted, delivered prematurely or died: soft stool, emaciation,
lustreless fur, ↓ activity, bradypnea, abnormally coloured intestinal contents,
gall bladder distention, watery/abnormally coloured bile, trace gastro-
intestinal haemorrhage and gas retention, and kidney discolouration were
observed.
1000 mg/kg bw/day: bw, bw loss (GD 6-18), mortality, splenic
congestion.
Developmental
NOAEL = 300 mg/kg bw/day
1000 mg/kg bw/day: ↑ incidence of abnormal location of posterior vena
cava.
Appendix II
Proposed Re-evaluation Decision - PRVD2019-10
Page 45
Study Type/
Animal/PMRA #
Study Results
No evidence of increased sensitivity of the young. Not teratogenic.
Note: litters available for examination were 13, 12, 11 and 4 at 0, 100, 300,
1000 mg/kg bw/day respectively.
Genotoxicity Studies
In vitro Bacterial Reverse
Mutation Assay
Salmonella typhimurium
strains TA 98, TA 100, TA
1535, TA 1537 and TA
1538;
E. Coli WP2uvrA
PMRA #1143910
Negative with and without activation.
In vitro Mammalian Gene
Mutation Assay
Chinese hamster V79 lung
cells
PMRA #1143911
Negative with and without activation.
In vitro Unscheduled DNA
Synthesis Assay
HeLa S3 cells
PMRA #1143909
Negative with and without activation.
In vitro Chromosome
Aberration Assay
Chinese hamster ovary cells
(CHO-K1)
PMRA #1143908
Negative with and without activation.
In vivo Micronucleus Assay
CD-1 Mouse
PMRA #621875
Negative at 5000 mg/kg bw (corn oil).
Neurotoxicity Studies
Acute Neurotoxicity
(gavage)
Sprague Dawley Rat
PMRA #2704596
Range-finding study - supplemental
No treatment-related findings were noted up to and including 2000 mg/kg
bw.
Acute Neurotoxicity
(gavage)
Sprague Dawley Rat
PMRA #2704607
NOAEL = 300 mg/kg bw (♂), 1000 mg/kg bw (♀)
≥1000 mg/kg bw: ↓ motor activity at 8 hrs post-dosing (♂).
2000 mg/kg bw: unkempt appearance on day 1 post-dosing (♀).
Appendix II
Proposed Re-evaluation Decision - PRVD2019-10
Page 46
Study Type/
Animal/PMRA #
Study Results
90-Day Neurotoxicity
(dietary)
Sprague Dawley Rat
PMRA #2704606
Range-finding study - supplemental
≥7500 ppm (691/762 mg/kg bw/day): bw, ↓ bwg, ↓ fc (♂).
15000 ppm (1359/1468 mg/kg bw/day): ↓ bw, ↓ bwg (♀).
90-Day Neurotoxicity
(dietary)
Sprague Dawley Rat
PMRA #2704608
NOAEL = 5000 ppm (359/407 mg/kg bw/day)
15000 ppm (1111/1212 mg/kg bw/day): bw, ↓ bwg, ↓ fc.
No evidence of neurotoxicity.
Special Studies (non-guideline)
28-Day Immunotoxicity
(dietary)
CD-1 Mouse
PMRA #2704592
Range-finding study
≥4000 ppm (with and without sRBC): slight bw loss or ↓ bw gain in first
four days of dosing, ↓ fc in first wk of dosing, ↑ liver wt.
7000 ppm (with and without sRBC): hunched posture, dull eyes,
piloerection, bw loss, ↓fc, ↑ phospholipid, ↑ cholesterol, ↑ plasma creatinine,
↑ BUN, ↑ kidney wt, enlargement of kidney, pallor, pelvic dilatation,
thickened capsule in kidney, granular appearance to the kidney surface,
kidney cysts, dilatation of the ureters.
7000 ppm (with sRBC): ↓ thymus wt.
28-Day Immunotoxicity
(dietary)
CD-1 Mouse
PMRA #2704593
NOAEL = 5000 ppm (1139 mg/kg bw/day)
≥1000 ppm (228 mg/kg bw/day): ↑ rel liver wt.
≥2000 ppm (449 mg/kg bw/day): abs liver wt.
5000 ppm (1139 mg/kg bw/day): ↓ bwg.
Uterotrophic Assay
(gavage for 3 days)
Sprague Dawley Juvenile ♀
Rat
PMRA #2704584
≥500 mg/kg bw/day: rel liver wt.
1000 mg/kg bw/day: bw, ↓ bwg, ↑ abs liver wt, ↑ rel kidney wt.
No treatment-related effects on uterine wt; positive controls demonstrated
expected results.
Hershberger Assay
(gavage for 10 days)
Sprague Dawley ♂ Rat
PMRA #2704597
1000 mg/kg bw/day: sporadic occurrences of stained anus and soft stools, ↓
bwg in anti-androgen assay only, ↑ liver wt, ↑ kidney wt.
No treatment-related effects on accessory sex organ wts; positive controls
demonstrated expected results.
Negative for androgenicity and anti-androgenicity.
Pubertal Development and
Thyroid Function Assay in ♂
Sprague Dawley
Juvenile/Peripubertal ♂ Rat
PMRA #2704605
≥500 mg/kg bw/day: clear material around mouth post-dosing, ↑ liver wt, ↓
ventral prostate wt, dorsolateral prostate wt , ↑ serum urea nitrogen, ↓
testosterone, hepatocellular hypertrophy, ↑ severity of hepatocellular mitotic
figures, renal tubular dilatation and degeneration, ↓ incidence of renal
mononuclear infiltrate, ↑ incidence of slight reduction in thyroid colloid
area, ↑ slight increase in thyroid follicular cell height.
Appendix II
Proposed Re-evaluation Decision - PRVD2019-10
Page 47
Study Type/
Animal/PMRA #
Study Results
1000 mg/kg bw/day: bw, ↓ bwg, delay for complete preputial separation,
two ♂ with small sex organs at necropsy, ↑ kidney wt, ↓ seminal vesicle wt,
↓ LABC wt, ↓ epididymis wt, ↓ testis wt, ↓ incidence of renal basophilic
tubules, renal mineralization.
No effect on serum T4, TSH.
Pubertal Development and
Thyroid Function Assay in ♀
(gavage for 20 days)
Sprague Dawley
Juvenile/Peripubertal ♀ Rat
PMRA #2704602
≥500 mg/kg bw/day: one mortality, ↑ liver wt, ↑ kidney wt, hepatocellular
hypertrophy and mitotic figures, renal tubular degeneration and/or dilatation,
↓ incidence of renal mononuclear infiltrate.
1000 mg/kg bw/day: bw, ↓ bwg, delay for incomplete vaginal opening, ↓
♀ cycling regularly, ↑ BUN, slight ↑ TSH, ↓ ovary wt, ↓ incidence of renal
basophilic tubules.
No effect on complete vaginal opening time, day of first estrus, estrous cycle
length, number of animals cycling, pathology of ovary, uterus or thyroid,
thyroid wt or serum T4.
Testosterone and Thyroid
Gland Mechanistic Study
(gavage for 30 days)
Sprague Dawley
Juvenile/Peripubertal ♂ Rat
PMRA #2704604
≥500 mg/kg bw/day: bw, ↓ bwg, delay in complete preputial separation, ↑
cholesterol, ↓ triglycerides, ↑ serum urea nitrogen, ↑hepatic enzymes
CYP2b, CYP4A, UGT, CYP3A, ↓ testosterone, ↑ rel liver wt, ↑ rel kidney
wt, ↓ abs LABC wt, hepatocellular hypertrophy, proliferation of smooth
endoplasmic reticulum, ↑ severity of focal basophilic renal tubules, renal
tubular degeneration, necrosis and dilatation, renal mineralization, ↓ colloid
area in thyroid, ↑ thyroid follicular cell height.
1000 mg/kg bw/day: one death (enlarged adrenal and testis and small
thymus at necropsy), ↓T4, ↓ rel LABC wt, ↓ abs epididymides wt, slight
renal papillary edema.
No effect on 17β-hydroxysteroid dehydrogenase activity in the testis.
Positive controls showed induction of hepatic microsomal enzymes
(CYP2B, CYP4A, UGT, CYP3A with phenobarbital, CYP4A with DEHP),
↑ liver wt, hepatocellular hypertrophy, reduced thyroid colloid area, ↑
thyroid follicular cell height; phenobarbital also had ↓T3, ↑TSH and slightly
↓ testosterone. Positive controls did not demonstrate anti-androgenic activity
at dose level tested.
In vitro Aromatase Inhibition
Assay
Human recombinant
aromatase (CYP19)
microsomes
PMRA #2704598
No inhibition of aromatase activity.
In vitro Androgen Receptor
Binding Assay
Ventral prostate cytosol from
Sprague Dawley rat
PMRA #2704599
No effect on specific binding of ligand in competitive binding experiment,
thus considered a non-binder.
In vitro Steroidogenesis
Assay
Precipitation at 100 μM and cytotoxicity at 30 μM
No effect on testosterone production up to 10 μM
Appendix II
Proposed Re-evaluation Decision - PRVD2019-10
Page 48
Study Type/
Animal/PMRA #
Study Results
H295R human
adrenocortical carcinoma
cells
PMRA #2704600
↑ estradiol production (1.7-1.8-fold) at 10 μM.
In vitro Estrogen Receptor
Binding Assay
Uterine cytosol from
Sprague Dawley rat
PMRA #2704601
No effect on specific binding of ligand in competitive binding experiment,
thus considered a non-binder.
ToxCast Studies
Cell-free high-throughput
assays
PMRA #2704603
Inhibition of radio-ligand binding was less than 50% for all concentrations
(0.02-50 μM ) for bovine and human estrogen receptors, bovine and human
progesterone receptors, rat and human androgen receptors and human
thyroid receptor-α.
Inhibition of human aromatase enzyme activity less than 50% for all
concentrations (0.009-20 μM).
ToxCast Studies
Cell-based high-throughput
assays
PMRA #2704603
Inactive for agonist activity at the human AR, human ER-α and the human
thyroid hormone receptor-β. Pyriproxyfen did not block (or antagonize) the
activity of established ligands at these receptor sites.
In vitro Estrogen Receptor
Transcriptional Activation
Assay
BG1 human ovarian
carcinoma cells
PMRA #2831625
EC
10
of 2.9 × 10-5M
Weakly estrogenic.
In vitro Estrogenic Activity
mtT/Se rat pituitary tumour
cells
PMRA #2831627
EC
10
of 5.5 × 10-5M
Weakly estrogenic.
In vitro Cytotoxic Response
(neutral red incorporation
assay)
Chinese hamster ovary K1
cells
PMRA #2831624
Pyriproxyfen showed increased cytotoxicity with time NRI
50
values were
377, 83 and 59 μM following 24, 48 and 72 hrs incubation resp. The
inclusion of fetal calf serum or bovine serum albumin diminished the
cytotoxicity suggesting protein binding. Pre-incubation of pyriproxyfen with
0, 4, 10 or 30% S9 fraction for 24 hrs also diminished the cytotoxicity
suggesting that the phase I metabolites were less toxic than pyriproxyfen.
In vitro Hepatotoxic
Response (MTT assay)
Hepatoma HepG2 cells
PMRA #2831626
Pyriproxyfen was cytotoxic at all concentrations (cell viability
approximately 50% at 1-10 ppm and <10% at 100 ppm) with both 24 and 48
hr incubation in MTT assay. Intracellular lipids were increased at ≥ 1 ppm
(using oil-red-O staining).
Appendix II
Proposed Re-evaluation Decision - PRVD2019-10
Page 49
Study Type/
Animal/PMRA #
Study Results
Pyriproxyfen Metabolite Studies
Acute Oral Toxicity
4'-OH-pyr
5"-OH-pyr
DPH-pyr
POPA
PYPAC
CD-1 mouse
PMRA #2704568
LD
50
>2000 mg/kg bw (methylcellulose) for all metabolites tested
≥1000 mg/kg bw:
5"-OH-pyr: ↓ spontaneous activity.
2000 mg/kg bw:
5"-OH-pyr: death in 1 out of 5 ♂, ataxic gait.
DPH-pyr: ↓ spontaneous activity, ataxic gait, prone position.
POPA: ↓ spontaneous activity, ataxic gait, prone position, lateral position,
irregular respiration.
PYPAC: ↓ spontaneous activity.
All clinical signs disappeared after 24 hrs.
Acute Oral Toxicity
2,5-OH-py
CD-1 mouse
PMRA #2704569
LD
50
= 1150 mg/kg bw (♂), 1000 mg/kg bw (♀) (methyl cellulose)
≥250 mg/kg bw: ↓ spontaneous activity (♂).
≥500 mg/kg bw: ataxic gait, mortality in 1 animal after 4 days (♂); ↓
spontaneous activity (♀).
≥1000 mg/kg bw: prone position, irregular respiration, hypothermia,
mortality after 24 hrs (♂); ataxic gait, irregular respiration, mortality within
2-24 hrs (♀).
≥2000 mg/kg bw: mortality within 2-24 hrs (♂).
Acute Oral Toxicity
2-OH-py
CD-1 mouse
PMRA #2704570
LD
50
= 124 mg/kg bw (♂), 166 mg/kg bw (♀) (distilled water)
≥50 mg/kg bw: ↓ spontaneous activity.
≥140 mg/kg bw: ataxic gait, irregular respiration; mortality in 4/5 animals
within 48 hrs (♂); mortality in 1 animal within 48 hrs (♀).
≥190 mg/kg bw: mortality in all animals within 24 hrs (♂); mortality in 4/5
animals within 72 hrs (♀).
≥270 mg/kg bw: mortality in all animals within 24 hrs (♀).
In vitro Bacterial Reverse
Mutation Assay
2,5-OH-py
Salmonella typhimurium
strains TA 98, TA 100, TA
1535, TA 1537 and TA
1538;
E. Coli WP2uvrA
PMRA #2704573
Negative with and without metabolic activation.
In vitro Bacterial Reverse
Negative with and without metabolic activation.
Appendix II
Proposed Re-evaluation Decision - PRVD2019-10
Page 50
Study Type/
Animal/PMRA #
Study Results
Mutation Assay
4'-OH-pyr
5"-OH-pyr
DPH-pyr
POPA
PYPAC
Salmonella typhimurium
strains TA 98, TA 100, TA
1535, TA 1537 and TA
1538;
E. Coli WP2uvrA
PMRA #2704574
In vitro Bacterial Reverse
Mutation Assay
2-OH-py
Salmonella typhimurium
strains TA 98, TA 100, TA
1535, TA 1537 and TA
1538;
E. Coli WP2uvrA
PMRA #2704575
Negative with and without metabolic activation.
Table 3 Reference Values for Use in Human Health Risk Assessment for Pyriproxyfen
Exposure Scenario
Study
Point of Departure and Endpoint
CAF1 or
Target MOE
Acute dietary
Not required as no endpoint of concern attributable to a single exposure was
identified.
Repeated dietary
Mouse oncogenicity
NOAEL = 16 mg/kg bw/day
Reduced survival
100
ADI = 0.2 mg/kg bw/day
Short- and intermediate-
term dermal
2 and inhalation3
(adults)
Rabbit
developmental
toxicity
NOAEL = 100 mg/kg bw/day
Increased abortions/premature
deliveries
300
Short- and intermediate-
term dermal
2 and inhalation3
(children)
Rat developmental
toxicity
NOAEL = 100 mg/kg bw/day
Reduced pup weight and equivocal
decrease in pup viability
100
Long-term dermal2 and
inhalation
3
Mouse oncogenicity
NOAEL = 16 mg/kg bw/day
Reduced survival
100
Non-dietary oral ingestion
(short-term)
90-Day rat toxicity
NOAEL = 24 mg/kg bw/day
Effects on liver and hematology
100
Short- and intermediate
term aggregate (adults)
Rabbit
developmental
toxicity
NOAEL = 100 mg/kg bw/day
Increased abortions/premature
deliveries
300
Appendix II
Proposed Re-evaluation Decision - PRVD2019-10
Page 51
Exposure Scenario
Study
Point of Departure and Endpoint
CAF1 or
Target MOE
Short- and intermediate
term aggregate (children)
Rat developmental
toxicity
NOAEL = 100 mg/kg bw/day
Reduced pup weight and equivocal
decrease in pup viability
100
Long-term aggregate
Mouse oncogenicity
NOAEL = 16 mg/kg bw/day
Reduced survival
100
Cancer
No evidence of carcinogenicity in mice or rats. A cancer risk assessment is
not required.
1 CAF (composite assessment factor) refers to a total of uncertainty and PCPA factors for dietary
assessments; MOE refers to a target MOE for occupational and residential assessments
2 Since an oral NOAEL was selected, a dermal absorption factor was used in a route-to-route extrapolation
Since an oral NOAEL was selected, an inhalation absorption factor of 100% (default value) was used in route-to-
route extrapolation.
Appendix III
Proposed Re-evaluation Decision - PRVD2019-10
Page 52
Appendix III Dietary Exposure and Risk Assessments
Summary of Dietary Exposure and Risk from Pyriproxyfen
Population Subgroup Chronic Dietary1 (Food Only)
Exposure (mg/kg bw/day) %ADI
General Population 0.009679 4.8
All Infants (<1 year old) 0.014614 7.3
Children 1-2 years old 0.025863 12.9
Children 3-5 years old 0.022463 11.2
Children 6-12 years old 0.014221 7.1
Youth 13-19 years old 0.008737 4.4
Adults 20-49 years old 0.008184 4.1
Adults 50-99 years old 0.007215 3.6
Females 13-49 years old 0.007887 3.9
1 Acceptable Daily Intake (ADI) of 0.2 mg/kg bw/day applies to the general population and all population
subgroups.
Appendix III
Proposed Re-evaluation Decision - PRVD2019-10
Page 53
Food Residue Chemistry Summary
Currently registered food uses of pyriproxyfen in Canada are greenhouse uses on tomato, pepper,
cucumber and eggplant. In addition, some products containing pyriproxyfen (for example,
NYLAR®) are registered for space, general surface, spot, and/or crack and crevice treatment,
provided that exposed food is covered or removed from the area being treated prior to
application.
The first comprehensive dietary risk assessment for pyriproxyfen was conducted in support of the
Proposed Registration Decision Document PRDD2006-04, Pyriproxyfen, published on
12 September 2006 for greenhouse use on tomato, cucumber and pepper. The assessment was
updated in 2011 for the use expansion to greenhouse eggplant. Further updates were conducted in
2013 and 2015 in support of the establishment of MRLs on various imported commodities.
The residue chemistry database for pyriproxyfen is complete and up-to-date for the registered
uses. The residue definition in plant and animal commodities was previously determined to be
pyriproxyfen per se for enforcement and risk assessment purposes. No change is being proposed
as a result of this re-evaluation. This residue definition is aligned with current residue definitions
established by the United States Environmental Protection Agency (USEPA), the European Food
Safety Authority (EFSA) and JMPR/Codex. It should be noted that, in addition to parent
pyriproxyfen, the USEPA has included the free and sulfate forms of the metabolite 4-OH-pyr in
its residue definition for animal commodities. However, USEPA concluded that there is no
expectation of finite residues in animal commodities and, therefore, waived the necessity of
establishing tolerances in animal commodities. There are currently no Canadian registrations on
major livestock feed items.
A gas chromatography with nitrogen-phosphorus detection (GC/NPD) method is available for
enforcement of pyriproxyfen MRLs. The limit of detection (LOD) and limit of quantitation
(LOQ) are 0.01 and 0.02 ppm, respectively. In addition, pyriproxyfen is included in the scopes of
multiresidue analytical methods used by the Canadian Food Inspection Agency (CFIA) and the
United States Department of Agriculture Pesticide Data Program (USDA PDP).
Appendix IV
Proposed Re-evaluation Decision - PRVD2019-10
Page 54
Appendix IV Occupational Mixer/Loader/Applicator and Postapplication Risk Assessment
Table 1 Occupational Mixer/Loader/Applicator Exposure and Risk Assessment
Scenarioa Application
Equipment Application
Rateb ATPDc
Exposured
(mg/kg bw/day)
MOE
Dermal
Inhalation
Combined
Dermale
Inhalationf
Combined
Mixer/Loader/Applicator: Single Layer, CR gloves
Indoor Structures
(crack & crevice, spot,
broadcast)
(T = 300)
MPHW 0.16 g a.i./L 40 L 6.9 × 10-3 2.6 × 10-5 6.9 × 10-3 14600 3810000 14500
Greenhouse
Ornamentals,
Tomatoes, Cucumbers,
Peppers, Eggplants
(T = 100)
MPHG 0.0464 g
a.i./Lg
3800 L 1.2 × 10-2 3.3 × 10
-4
1.3 × 10
-2
8100 300500 7900
MPHW
150 L
8.2 × 10-5
3.9 × 10-6
8.6 × 10-5
1218400 25429800 1162700
Backpack 4.7 × 10-4 1.3 × 10
-5
5.4 × 10-6 211100 18509300 208700
ATPD = Volume treated or handled per day; MOE = Margin of Exposure; Single layer = long-sleeved shirt, long pants; MPHG = Mechanically Pressurized Handgun; MPHW =
Manually-Pressurized Hand wand; T = Target MOE; CR = chemical-resistant
a The application method or scenario where the application equipment may be used.
b Maximum application rates were used for each scenario/application equipment.
c Volume treated or handled per day values.
d Exposure = Unit Exposure (µg/kg a.i.) × ATPD × Application Rate × dermal absorption (100%) / Body Weight (80 kg). Unit exposure values from PHED or Krolski, 2014.
e Dermal MOEs for short-to-intermediate term exposure scenarios are based on a NOAEL of 100 mg/kg bw/day (target MOE is 300) from an oral rabbit developmental toxicity
study.
f Inhalation MOEs for short-to-intermediate term exposure scenarios are based on a NOAEL of 100 mg/kg bw/day (target MOE is 300) from an oral rabbit developmental toxicity
study.
g Application rate to greenhouse ornamentals is 29.7 g a.i./ha, but only highest rate to all greenhouse crops (92.8 g a.i./ha) was shown in this risk assessment.
Table 2 Occupational Postapplication Exposure and Risk Assessment
Use(s) Ratea
(g/ha) NAPS Interval
(days) Activityb TC
(cm2/hr)
DFRc Inputs
Day 0 Dermal Estimatesf
REI
(days)
Peak Disp DFR0f
Exposured (µg/kg
bw/day)
MOEe
Cut Flowers 29. 7 4 14
Pruning,
Disbudding, Hand
Harvesting
4000 25% 2.3% 0.19 77.8 200 0.5
Appendix IV
Proposed Re-evaluation Decision - PRVD2019-10
Page 55
Use(s) Ratea
(g/ha) NAPS Interval
(days) Activityb TC
(cm2/hr)
DFRc Inputs
Day 0 Dermal Estimatesf
REI
(days)
Peak Disp DFR0f
Exposured (µg/kg
bw/day) MOEe
GH Ornamentals
(Non-cut flowers)
All activities
230 4.47 3580
GH tomatoes,
peppers,
cucumbers,
eggplants
92.8 1400 0% 0.93 130 120
NAPS = Number of Applications per Season, TC = Transfer Coefficient, DFR = Dislodgeable Foliar Residue, Peak = Peak DFR as Percent of Application Rate, Disp = Percent
Dissipation per Day, DFR0 = Day 0 DFR (ug/cm2), MOE = Margin of Exposure, REI = Restricted-Entry Interval, GH = Greenhouse
a Maximum application rates were used.
b Activity with the highest TC for each crop was included in this table.
c The default peak DFR value of 25% of the application rate was assumed and a dissipation rate of 2.3%/day was assumed for greenhouse ornamental scenarios, a dissipation rate
of 0%/day was assumed for greenhouse vegetable scenarios
d Dermal exposure on Day 0 after application = TC × DFR × 8 hours/day × Dermal Absorption (100%) / Body Weight (80 kg).
e Dermal MOEs for long-term exposure scenarios are based on a NOAEL of 16 mg/kg bw/day (target MOE is 100) from an oral mouse oncogenicity study.
f Calculated for day 0 after the last application.
Appendix V
Proposed Re-evaluation Decision - PRVD2019-10
Page 56
Appendix V Residential Applicator and Postapplication Risk Assessment
Table 1 Residential Applicator Exposure and Risk Assessment
Scenarioa Application Rateb ATPD/Amount
Handled per Dayc
Absorbed Dose (mg/kg bw/day)d
MOE (T = 300)
Dermal Inhalation Dermale Inhalationf Combined
Spot, crack and crevice
(Pressurized product can)
0.000075 kg
a.i./can 0.5 can 0.0003824 0.0000031 260000 32000000 260000
Spot, crack and crevice
(trigger spray bottle)
0.000088 kg
a.i./can
0.5 bottle
0.0001032
7.15 × 10-8
1100000
1500000000
1100000
Broadcast (trigger spray
bottle)
1 bottle
0.0002063
1.43 × 10-5
530000
760000000
530000
Treated pets (shampoo)
0.0001995 kg
a.i./pet 2 pets
0.0219911 0.0000032 4500 31000000 4500
Treated pets (spot-on)g
0.0000976 kg
a.i./pet 0.0006455 NA 150000 NA NA
ATPD = Area Treated Per Day; MOE = Margin of Exposure; T = Target MOE; NA = Not Applicable
a The application method or scenario where the application equipment may be used.
b Maximum rates were used for each scenario/application equipment.
c Volume treated or handled per day values.
d Absorbed Dose = Unit Exposure (µg/kg a.i.) × ATPD × Application Rate × Dermal Absorption (100%) / Body Weight (80 kg). Unit exposure values from USEPA, 2012.
e Dermal MOEs for short-to-intermediate term exposure scenarios are based on a NOAEL of 100 mg/kg bw/day (target MOE is 300) from an oral rabbit developmental toxicity study.
f Inhalation MOEs for short-to-intermediate term exposure scenarios are based on a NOAEL of 100 mg/kg bw/day (target MOE is 300) from an oral rabbit developmental toxicity study.
g Applicator was wearing gloves in the study used to determine exposure for this scenario. Inhalation exposure is considered to be negligible for spot-on applications (USEPA, 2012).
Table 2 Residential Postapplication Dermal Exposure and Risk Assessment
Exposure Scenario Lifestage
TR a
(µg/cm
2
)
TC b
(cm
2
/hr)
ET c
(hr/day)
Dermal Dose d
(mg/kg bw/day)
MOE e
Applied by commercial applicator
Indoor
Environments
Broadcast Soft surface
Adult
0.0288
6800
8
0.01958
5100
Children 1<2
1800
4
0.01885
5300
Hard surface
Adult
0.0384
6800
2
0.00653
15000
Children 1<2
1800
2
0.01257
8000
Perimeter/Spot Soft surface
Adult
0.0144
6800
8
0.00979
10000
Children 1<2 1800 4 0.00943 11000
Hard surface
Adult
0.0192
6800
2
0.00326
31000
Appendix V
Proposed Re-evaluation Decision - PRVD2019-10
Page 57
Exposure Scenario Lifestage
TR a
(µg/cm
2
)
TC b
(cm
2
/hr)
ET c
(hr/day)
Dermal Dose d
(mg/kg bw/day)
MOE e
Children 1<2
1800
2
0.00628
16000
Crack and crevice Soft surface
Adult
0.0029
6800
8
0.00196
51000
Children 1<2
1800
4
0.00189
53000
Hard surface
Adult
0.0038
6800
2
0.00065
150000
Children 1<2
1800
2
0.00126
80000
Applied by residential applicator
Indoor
Environments
Broadcastf
(Trigger pump
sprayer)
Soft surface
Adult
0.0372
6800
8
0.02530
4000
Children 1<2
1800
4
0.02435
4100
Hard surface
Adult
0.0496
6800
2
0.00843
12000
Children 1<2
1800
2
0.01623
6200
Perimeter/Spot
(Pressurized Product)
Soft surface
Adult
0.750
1800
8
0.01338
7500
Children 1<2
6800
4
0.01288
7800
Hard surface
Adult
1.000
1800
2
0.00446
22000
Children 1<2
6800
2
0.00859
12000
Treated Pets
Shampoo (dog)
Small
Adult
0.0013
5200
0.77
0.07
1500
Children 1<2
1400
1
0.17
590
Medium
Adult
0.0006
5200
0.77
0.03
3500
Children 1<2
1400
1
0.07
1400
Large
Adult
0.0004
5200
0.77
0.02
5500
Children 1<2
1400
1
0.05
2200
Spot-on (dog)
Small
Adult
0.0007
5200
0.77
0.03257
3100
Children 1<2
1400
1
0.08281
1200
Medium
Adult
0.0003
5200
0.77
0.01396
7200
Children 1<2
1400
1
0.03549
2800
Large
Adult
0.0002
5200
0.77
0.00888
11000
Children 1<2
1400
1
0.02259
4400
Spot-on (cat)
Small
Adult
0.0005
5200
0.77
0.02289
4400
Children 1<2
1400
1
0.05821
1700
Medium
Adult
0.0003
5200
0.77
0.01373
7300
Children 1<2
1400
1
0.03492
2900
Large
Adult
0.0002
5200
0.77
0.00858
12000
Children 1<2
1400
1
0.02183
4600
TR = Transferable residue; TC = Transfer coefficient; ET = Exposure time; MOE = Margin of exposure
a Transferable residues calculated based on the application rate and the exposure scenario using default fraction transferred values of 2% for pets, 6% for soft surfaces and 8% for hard surfaces
(USEPA, 2012). Maximum application rates were used.
b Transfer coefficient default values from the USEPA Residential SOPs (USEPA, 2012) were used .
c Exposure time default values from the Residential SOPs (USEPA, 2012) were used.
d Dermal dose = TR × TC × ET/BW (kg) Body weights of 80 and 11 kg were used for adults and children (1 <2 years) respectively, as stated in the USEPA Residential SOPs (USEPA, 2012). Dermal
absorption was assumed to be 100%.
e MOE = NOAEL/ exposure, based on a NOAEL of 100 mg/kg bw/day from an oral rabbit developmental toxicity study and a target MOE of 300 for adults, and a NOAEL of 100 mg/kg bw day from
an oral rat developmental toxicity study and a target MOE of 100 for children, applicable to short- to intermediate-term exposure scenarios.
f Broadcast application is expected to result in higher exposure relative to perimeter/spot application, therefore only broadcast application of trigger pump sprayer product is presented
Appendix V
Proposed Re-evaluation Decision - PRVD2019-10
Page 58
Table 3 Residential Postapplication Incidental Oral Exposure and Risk Assessment for Children (1<2 Years old)
Exposure Scenario
Hand Residue (mg/hour) or Object
Residue (µg/cm
2
)
a
ETb
(hr/day)
Oral Dosec
(mg/kg bw/day)
Incidental Oral MOEd
Applied by commercial applicator
Indoor Environments
HtM Broadcast
Soft surface
0.0039
4
0.00018
140000
Hard surface
0.0052
2
0.00012
200000
HtM Perimeter/Spot
Soft surface
0.0019
4
0.00009
270000
Hard surface
0.0026
2
0.00006
410000
HtM Crack and Crevice
Soft surface
0.0004
4
0.00002
1400000
Hard surface
0.0005
2
0.00001
2000000
OtM Broadcast
Soft surface
0.0288
4
0.00038
64000
Hard surface
0.0384
2
0.00025
96000
OtM Perimeter/Spot
Soft surface
0.0144
4
0.00019
130000
Hard surface
0.0192
2
0.00013
190000
OtM Crack and Crevice
Soft surface
0.0029
4
0.00004
640000
Hard surface
0.0038
2
0.00003
960000
Applied by residential applicator
Indoor Environments
HtM Broadcast
(Trigger pump sprayer)
Soft surface
0.0050
4
0.00023
110000
Hard surface
0.0067
2
0.00015
160000
HtM Perimeter/Spot
(Pressurized Product)
Soft surface
0.1013
4
0.00012
200000
Hard surface
0.1350
2
0.00008
300000
OtM Broadcast
(Trigger pump sprayer)
Soft surface
0.0372
4
0.00049
49000
Hard surface
0.0496
2
0.00032
74000
OtM Perimeter/Spot
(Pressurized Product)
Soft surface
0.7500
4
0.00026
93000
Hard surface
1.0000
2
0.00017
140000
Treated Pets
HtM Shampoo (dog)
Small
0.0372
1
0.00042
57000
Medium
0.0160
1
0.00018
130000
Large
0.0102
1
0.00012
210000
HtM Spot-on (dog)
Small
0.0182
1
0.00021
120000
Medium
0.0078
1
0.00009
270000
Large
0.0050
1
0.00006
420000
HtM Spot-on (cat)
Small
0.0128
1
0.00015
160000
Medium
0.0077
1
0.00009
270000
Large
0.0048
1
0.00005
440000
ET = Exposure time; MOE = Margin of exposure; HtM = Hand-to-Mouth; OtM = Object-to-Mouth
a Based on the dermal postapplication exposure from indoor applications without the body weight × fraction of a.i. on hands compared to the body (0.15)/(4 hr × 4 intervals/hr).
b Exposure time based on default values from the USEPA (USEPA, 2012).
c Oral dose = [Hand Residue (mg/cm2) × (Fraction of hand mouthed/event (0.13) × Surface Area of one hand (150 cm2)) × (Exposure Time (hr) × Replenishment Intervals (4/hr)) × (1 (1 Saliva
Extraction Factor (0.48)) Number events per hour (20)/Replenishment Intervals (4/hr))]/ Body Weight (11 kg) or oral dose = Object Residue (µg/cm2) × Conversion factor (mg/µg) × Surface area of object mouthed (10
cm2/event) × [Exposure time (hrs) × Number of replenishments per hour (4)] × [1-(1-Saliva Extraction Factor (0.48))Frequency of OtM contacts per hour (14)/Number of replenishments per hour (4)] / Body Weight (11 kg)
d MOE = NOAEL / exposure, based on a NOAEL of 24 mg/kg bw/day from a 90-day oral rat toxicity study and a target MOE of 100 for children, applicable to short-term exposure scenarios.
Appendix VI
Proposed Re-evaluation Decision - PRVD2019-XX
Page 59
Appendix VI Aggregate Risk Assessment
Table 1 Aggregate Exposure and Risk Assessment
Scenario Lifestage
Dermal
Exposurea
(mg/kg
bw/day)
Inhalation
Exposureb (mg/kg
bw/day)
Incidental Oral
Exposurec,d
(mg/kg bw/day)
Chronic Dietary
Exposuree (mg/kg
bw/day)
Aggregate
MOEf
Indoor Environments
(Commercially applied
Broadcast)
Soft surfaces
Adult
0.01958
NA
NA
0.007822
3650
Children (1< 2 yrs)
0.01885
NA
0.00038
0.025864
2220
Hard surfaces
Adult
0.00653
NA
NA
0.007822
6970
Children (1< 2 yrs)
0.01257
NA
0.00025
0.025864
2590
Indoor Environments
(Domestically applied
Perimeter/Spot with
pressurized product)
Soft surfaces
Adult
0.01376
3.10 × 10-6
NA
0.007822
4630
Children (1< 2 yrs)
0.01288
NA
0.00026
0.025864
2560
Hard surfaces
Adult
0.00484
3.10 × 10-6
NA
0.007822
7890
Children (1< 2 yrs)
0.00859
NA
0.00017
0.025864
2890
Indoor Environments
(Domestically applied
Broadcastg with trigger
pump sprayer)
Soft surfaces
Adult
0.02549
1.00 × 10-7
NA
0.007822
3000
Children (1< 2 yrs)
0.02435
NA
0.00049
0.025864
1970
Hard surfaces
Adult
0.00862
1.00 × 10-7
NA
0.007822
6080
Children (1< 2 yrs)
0.01623
NA
0.00032
0.025864
2360
Treated Pets
(shampoo)
Adult
0.08856
3.19 × 10-6
NA
0.007822
1040
Children (1< 2 yrs)
0.16927
NA
0.00042
0.025864
510
Treated Pets
(spot-on)
Adult
0.03321
NA
NA
0.007822
2440
Children (1< 2 yrs)
0.08281
NA
0.00021
0.025864
920
NA = Not Applicable; MOE = Margin of Exposure; yrs = years
a Combined dermal exposure resulting from application (when applicable) and postapplication exposure.
b Inhalation exposure resulting from application exposure, when applicable.
c Incidental oral exposure reflects either hand-to-mouth exposure for treated pets or object-to-mouth exposure for indoor environments. Incidental oral exposure is only applicable to children 1 <2 years
old.
d Treated indoor environments may result in both hand-to-mouth and object-to-mouth exposure. Since object-to-mouth exposure is higher, object-to-mouth exposure was aggregated.
e Chronic dietary exposure (food only) is based on information provided in the dietary risk assessment.
f Aggregate MOE = Aggregate NOAEL/Aggregate Exposure (dermal+inhalation+incidental oral+dietary), based on an aggregate NOAEL of 100 mg/kg bw/day from an oral rabbit developmental
toxicity study and a target MOE of 300 for adults, and an aggregate NOAEL of 100 mg/kg bw day from an oral rat developmental toxicity study and a target MOE of 100 for children (1<2 years).
g Broadcast application is expected to result in higher exposure relative to perimeter/spot application, therefore only broadcast application of trigger pump sprayer product is presented.
Appendix VII
Proposed Re-evaluation Decision - PRVD2019-10
Page 60
Appendix VII Label Amendments for Products Containing Pyriproxyfen
The label amendments presented below do not include all label requirements for individual end-
use products, such as first aid statements, disposal statements, precautionary statements and
supplementary protective equipment. Information on labels of currently registered products
should not be removed unless it contradicts the label statements provided below.
I. For Technical Grade of the Active Ingredient and Manufacturing
Concentrate:
The following must appear under a section titled “ENVIRONMENTAL
PRECAUTIONS”:
“TOXIC to aquatic organisms.”
“DO NOT discharge effluent containing this product into sewer systems, lakes, streams,
ponds, estuaries, oceans or other waters.”
II. For Commercial End-Use Products for Greenhouse Uses:
1) Remove the following under the "PRECAUTIONS" section:
This product contains a petroleum distillate which is moderately to highly toxic to
aquatic organisms. Avoid contamination of aquatic systems during application. Do not
contaminate these systems through direct application, disposal of waste or cleaning of
equipment.”
2) Under the section ENVIRONMENTAL HAZARDS”, remove the following:
“This pesticide is toxic to fish and aquatic invertebrates. Do not apply directly to water, or to
areas where surface water is present.”
And replace with the following:
This product contains an active ingredient and aromatic petroleum distillates which are toxic to
aquatic organisms.
3) Change the heading “ENVIRONMENTAL HAZARDS” to “ENVIRONMENTAL
PRECAUTIONS”
4) Under “DIRECTIONS FOR USE: MIXING INSTRUCTIONS (Booklet label)”:
Add:
"As this product is not registered for the control of pests in aquatic systems, DO NOT use
to control aquatic pests."
Appendix VII
Proposed Re-evaluation Decision - PRVD2019-10
Page 61
“DO NOT contaminate irrigation or drinking water supplies or aquatic habitats by
cleaning of equipment or disposal of wastes.”
III. COMMERCIAL-CLASS PRODUCTS (with specific Registration Numbers)
1) For the label with the greenhouse uses (Registration Number 28414):
Statements related to the personal protective equipment (PPE) and restricted-entry
interval (REI) are proposed to be updated to current wording.
o For PPE, replace:
“Wear coveralls or long-sleeved shirt and long pants, rubber boots, goggles,
gloves (rubber, PVC, neoprene or nitrile) and hat during mixing, loading, cleanup
and application.”
with:
“Wear a long-sleeved shirt, long pants, chemical-resistant gloves (rubber, PVC,
neoprene or nitrile), socks and shoes during mixing, loading, application, clean-up
and repair.”
o For REI, replace:
“DO NOT re-enter treated areas within 12 hours.”
with:
DO NOT enter or allow worker entry into treated areas during the restricted
entry interval (REI) of 12 hours.”
Statements are proposed to prohibit application using handheld mist blower or handheld
fogging equipment, as data are not available to assess these uses.
Add to Directions For Use: “Do not apply greenhouse processing water containing this
product to field crops (food and feed).”
2) For the label with directions to control fleas in indoor environments (Registration
Number 25490):
The following PPE as per the occupational risk assessment are proposed to be added to
the label:
“Wear a long-sleeved shirt, long pants, chemical-resistant gloves, socks and shoes
during mixing, loading, application, clean-up and repair.”
Statements related to entry after application are proposed to be updated to current
wording as follows:
BROADCAST APPLICATION: DO NOT allow people or pets to enter treated
areas for 2 hours or until sprays have dried.
SPOT AND CRACK AND CREVICE APPLICATION: DO NOT allow people or
Appendix VII
Proposed Re-evaluation Decision - PRVD2019-10
Page 62
pets to enter treated areas until sprays have dried.”
Best practice statements to update the precautionary label directions as per PRO2018-04
are proposed:
Under “DIRECTIONS FOR USE”:
DO NOT apply to mattresses, linens, toys or clothing.”
DO NOT apply to overhead areas or in confined spaces without appropriate
respiratory and eye protection.”
DO NOT allow spray to drip or allow drift onto non-target surfaces; any spray
residue on non-target areas must be removed by the applicator.”
DO NOT apply as a space spray.
“Use a coarse, low pressure spray not exceeding 345 kPa (50 psi).”
Under “PRECAUTIONS”:
DO NOT apply to surfaces that may come into contact with food/feed.”
“Cover or remove all food/feed. Cover all food/feed processing surfaces,
equipment and utensils or thoroughly wash following treatment.”
“Ventilate treated areas after application either by opening windows and doors or
through use of air exchange/ventilation systems confirmed to be operational. Use
fans where required to aid in the circulation of air.”
DO NOT apply when people or pets are present.”
IV. DOMESTIC-CLASS PRODUCTS
End-use products with instructions for indoor applications to control fleas and which are co-
formulated with tetramethrin or d-phenothrin have conflicting application directions as a result of
label changes required for the re-evaluation of tetramethrin or d-phenothrin. Therefore, label
changes are proposed to clarify application directions for specific use sites while ensuring
consistency with the evaluations of tetramethrin and d-phenothrin.
These label amendments include:
Removal of label statements restricting application to crack and crevice and perimeter
applications. Directions for spot treatment are proposed to remain for products co-
formulated with tetramethrin.
Application directions, including clarification of rates, are proposed to be added for
specific uses on the current labels, that is, for pet bedding, indoor surfaces (rugs, carpets
and drapes) and upholstery.
In addition, best practice statements to update the precautionary label directions as per
PRO2018-04 are proposed:
Under “DIRECTIONS FOR USE”:
Appendix VII
Proposed Re-evaluation Decision - PRVD2019-10
Page 63
DO NOT apply to mattresses, linens, toys or clothing.”
DO NOT apply to overhead areas or in confined spaces without appropriate respiratory
and eye protection.”
DO NOT allow spray to drip or allow drift onto non-target surfaces; any spray residue
on non-target areas must be removed by the applicator.”
DO NOT apply as a space spray.”
“Use a coarse, low pressure spray not exceeding 345 kPa (50 psi).”
Under “PRECAUTIONS”:
DO NOT apply to surfaces that may come into contact with food/feed.”
“Cover or remove all food/feed. Cover all food/feed processing surfaces, equipment and
utensils or thoroughly wash following treatment.”
“Ventilate treated areas after application either by opening windows and doors or through
use of air exchange/ventilation systems confirmed to be operational. Use fans where
required to aid in the circulation of air.”
DO NOT apply when people or pets are present.”
DO NOT allow people or pets to enter treated areas [“until sprays have dried” or re-
entry time currently stated on label].”
Remove from all domestic-class indoor application labels:
“[Retreat/Repeat] as necessary.
For spot-on, pyriproxyfen products registered for use on cats and dogs, the following
precautionary label directions as per PRO2018-01 are proposed:
For products used on dogs:
“Monitor your dog after application. Side effects may include: skin irritation such as
redness or scratching; changes in behaviour such as agitation or lethargy; or
gastrointestinal effects such as vomiting or loss of appetite. If these or other side effects
occur consult your veterinarian or [Registrant at 1-800-number].”
For products used on cats:
“Monitor your cat after application. Side effects may include: skin irritation such as
scratching or hair loss at the application site, or changes in behaviour such as agitation or
lethargy. Gastrointestinal effects such as drooling, vomiting, or loss of appetite may also
occur. If these or other side effects occur consult your veterinarian or [Registrant at 1-
800-number].”
The following label improvements for spot-on products are proposed:
Remove label language that allows re-application of the product before the end of the
effective control period. For example, products that are labeled as providing four weeks
of control, should not have statements such as “Reapply after one week if necessary”.
Appendix VII
Proposed Re-evaluation Decision - PRVD2019-10
Page 64
Add label language to contraindicate use of other flea control products with the same
active ingredients as the spot-on (For example: “This product contains [name of active
ingredient(s)]. Do not apply another pest control product such as a shampoo, collar, or
powder which contains [name of active ingredient(s)] to the treated animal when using
[name of spot-on product]”).
References
Proposed Re-evaluation Decision - PRVD2019-10
Page 65
References
Information Considered in the Chemistry Assessment
A. Studies/Information Submitted by Registrant
PMRA
Document
Number
Reference
1854753
1987, [CBI removed] Supplemental Volume 4 Response to Ag Canada Pesticides
Directorate Review Comments Product Chemistry Data - Ultraviolet-Visible
Absorption Spectra Determination of Sumilarv, DACO: 2.14.12 CBI
1854760
1989, [CBI removed] Sumilarv - Product Identity and Composition, DACO:
2.11.2,2.11.3,2.11.4 CBI
1854801
1989, [CBI removed] Sumilarv - Physical and Chemical Characteristics, DACO:
2.14.1,2.14.10,2.14.11,2.14.12,2.14.13,2.14.14,2.14.2,2.14.3,2.14.4,2.14.6,2.14.7,
2.14.9 CBI
1855168
1989, [CBI removed] Sumilarv - Product Identity and Composition (Revised) -
Product Identity, Description of Beginning Materials and Manufacturing Process,
Impurities, DACO: 2.11,2.14.1,2.14.13,2.14.2,2.14.4,2.3,2.5,2.6,2.7,2.8,2.9 CBI
2704557
2016, Batch Analysis of Pyriproxyfen Technical Grade, DACO: 2.13.3,2.13.4 CBI
Information Considered for the Toxicological Assessment
A. List of Studies/Information Submitted by Registrant
3.0 Human Health
PMRA
Document
Number
Reference
621875 1991, Mouse Micronucleus Test On S-31183, DACO: 4.5.7
1143882 1991, S31183: Toxicity Study by Oral (capsule) Administration to Beagle Dogs
for 52 weeks., DACO: 4.3.1,4.3.2
1143883 1998, Sumilarv-Subacute Inhalation Toxicity Study of S-31183 in Rats., DACO:
4.3.6
1143884 1991, SUMILARV: COMBINED CHRONIC TOXICITY AND
ONCOGENICITY STUDY IN RATS WITH S-31183, DACO: 4.4.1,4.4.2
1143889 1987, SUMILARV-ACUTE ORAL TOXICITY OF S-31183 IN RATS, DACO:
4.2.1
1143893 1987, SUMILARV-ACUTE DERMAL TOXICITY OF S-31183 IN RATS,
DACO: 4.2.2
References
Proposed Re-evaluation Decision - PRVD2019-10
Page 66
PMRA
Document
Number
Reference
1143894 1989, ACUTE INHALATION TOXICITY OF SUMILARV, DACO: 4.2.3
1143896 1987, SUMILARV-PRIMARY EYE AND SKIN IRRITATION TESTS WITH S-
31183 IN RABBITS, DACO: 4.2.4,4.2.5
1143897 1987, SUMILARV- SKIN SENSITIZATION TEST WITH S-31183 IN GUINEA
PIGS, DACO: 4.2.6
1143898 1988, SUMILARV- THREE MONTH ORAL TOXICITY STUDY OF S-31183
IN DOGS, DACO: 4.3.1,4.3.2
1143899 1989, SUMILARV- SUBCHRONIC TOXICITY STUDY WITH S-31183 IN
RATS, DACO: 4.3.1
1143902 1991, SUMILARV: COMBINED CHRONIC TOXICITY AND
ONCOGENICITY STUDY IN RATS WITH S-31183 (343-214), DACO:
4.4.1,4.4.2
1143903 1991, SUMILARV: COMBINED CHRONIC TOXICITY AND
ONCOGENICITY STUDY IN RATS WITH S-31183, DACO: 4.4.1,4.4.2
1143904 1991, A DIETARY 2-GENERATION (1 LITTER) REPRODUCTION STUDY
OF S-31183 IN THE RAT (CONT'D ON ROLL#1036), DACO: 4.5.1
1143905 1991, A DIETARY 2-GENERATION (1 LITTER) REPRODUCTION STUDY
OF S-31183 IN THE RAT, DACO: 4.5.1
1143906 1989, SUMILARV-STUDY OF S-31183 BY ORAL ADMINISTRATION
DURING THE PERIOD OF FETAL ORGANOGENESIS IN RABBITS (376),
DACO: 4.5.2
1143907 1988, SUMILARV-STUDY OF S-31183 BY ORAL ADMINISTRATION
DURING THE PERIOD OF FETAL ORGANOGENESIS IN RATS, DACO:
4.5.2
1143908 1989, SUMILARV-IN VITRO CHROMOSOMAL ABERRATION TEST OF
PYRIPROXYFEN IN CHINESE HAMSTER OVARY CELLS (CHO-K1),
DACO: 4.5.4
1143909 1988, SUMILARV- ASSESSMENT OF UNSCHEDULED DNA REPAIR
SYNTHESIS IN MAMMALIAN CELLS AFTER EXPOSURE TO S-31183,
DACO: 4.5.4
1143910 SUMILARV- REVERSE MUTATION TEST OF S-31183 IN BACTERIAL
SYSTEMS (153;NNT-80-0034), DACO: 4.5.4
1143911 1990, SUMILARV- IN VITRO GENE MUTATION TEST OF S-31183 IN V79
CHINESE HAMSTER CELLS, DACO: 4.5.4
References
Proposed Re-evaluation Decision - PRVD2019-10
Page 67
PMRA
Document
Number
Reference
1143912 1991, SUMILARV-ONCOGENICITY STUDY IN MICE WITH S-31183 (343-
215), DACO: 4.4.2
1143930 1991, SUMILARV- ONCOGENICTITY STUDY IN MICE WITH S-31183,
DACO: 4.4.2
1143941 SUMILARV- METABOLISM OF S-31183 IN RATS (NNM-80-
0001;807;810;811), DACO: 4.5.9
1143949 1998, SUMILARV- METABOLISM OF S-31183 IN RATS (TISSUE
DISTRIBUTION STUDY), DACO: 4.5.9
1159013 ONCOGENICITY STUDY IN MICE (343-215,JULY 23,1991)(CRITERIA
UTLIZED BY THE PATHOLOGIST IN DETERMINING THE GRADING
SYSTEM FOR HISTOPATHOLOGICAL LESIONS)(SUMILARV), DACO:
4.4.2
1159014 RABBIT TERATOLOGY STUDY (NNT-80-0003,AUGUST
30,1989)(ADDITIONAL DATA AND APPENDICES AS REQUESTED ON
VARIOUS POINTS SEE MICROFILM FOR EXACT DETAILS)(SUMILARV),
DACO: 4.5.2
1159015 RAT TERATOLOGY STUDY (NNT-80-0029,MARCH
28,1988)(ADDITIONAL DATA AS REQUESTED SEE MICROFILM FOR
MORE DETAIL)(SUMILARV), DACO: 4.5.2
1159016 METABOLISM STUDY IN RATS (NNM-80-0001,APRIL
14,1988)(ADDITIONAL DATA ON: NEW "QUALITY ASSURANCE
STATEMENT)(807,810,811)(SUMILARV), DACO: 4.5.9
1159046 1987, ACUTE ORAL TOXICITY IN RATS AMENDMENT TO FINAL
REPORT NO. NNT-70-0005, FEBRUARY 4, 1987 (INDIVIDUAL TOXIC
SIGNS/BODY WEIGHT/GROSS PATHOLOGY
FINDINGS)(ACT86033)(SUMILARV), DACO: 4.2.1
1159057 1987, ACUTE DERMAL TOXICITY IN RATS AMENDMENT TO FINAL
REPORT NO. NNT-70-0006,FEBRUARY 4,1987 (INDIVIDUAL BODY
WEIGHT/GROSS PATHOLOGY FINDINGS)(ACT86034)(SUMILARV),
DACO: 4.2.2
1159068 1994, ACUTE INHALATION TOXICITY IN RATS AMENDMENT TO FINAL
REPORT NO. NNT-70-0022,DECEMBER 3,1989 (PARTICLE
SIZE,INDIVIDUAL TOXIC SIGNS/BODY WEIGHT/GROSS PATHOLOGY
FINDINGS/INDIVIDUAL HISTOPATHOLOGICAL
EXAMINATION)(636)(SUMILARV), DACO: 4.2.3
References
Proposed Re-evaluation Decision - PRVD2019-10
Page 68
PMRA
Document
Number
Reference
1159075 1994, SUBCHRONIC TOXICITY IN RATS (343-208)(ADDITIONAL
INDIVIDUAL ANIMAL ON OPHTHALMOSCOPIC
EXAMINATIONS)(SUMILARV), DACO: 4.3.1
1159076 1994, 52-WEEK TOXICITY IN DOGS (91/0776,AUGUST 1,1991)(CRITERIA
UTILIZED BY THE PATHOLOGIST IN DETERMINING THE GRADING
SYSTEM FOR HISTOPATHOLOGICAL LESIONS)(SUMILARV), DACO:
4.4.1
1159077 1994, COMBINED CHRONIC TOXICITY AND ONCOGENICITY IN RATS
(343-214,SEPTEMBER 6,1991)(ADDITIONAL DATA ON: CRITERIA
UTILIZED BY THE PATHOLOGIST IN DETERMINING THE GRADING
SYSTEM FOR HISTOPATHOLOGICAL LESIONS AND DATES OF
HISTORICAL CONTROL STUDIES)(SUMILARV) [contains a letter], DACO:
0.8,4.4.1,4.4.2
1164935 1994, SUMILARV- RESPONSE TO EPA REVIEW OF CHRONIC TOXICITY
AND/OR ONCOGENICITY STUDIES OF SUMILARV (S-31183) IN RATS
AND MICE., DACO: 4.4.1,4.4.2
1164978 1990, FINAL REPORT: SUMILARV-SUBCHRONIC TOXICITY STUDY IN
MICE., DACO: 4.3.1
1164979 1993, SUMILARV- 21 DAY DERMAL TOXICITY STUDY IN RATS WITH S-
31183., DACO: 4.3.4
1164980 1996, RESPONSE TO HEALTH CANADA QUESTIONS REGARDING THE
EVALUATION CRITERIA IN THE TERATOGENICITY/DEVELOPMENTAL
TOXICITY STUDY OF SUMILARV (S-31183) IN RABBITS. DATE
COMPLETED: FEBRUARY 12,1996.(VOLUME 43;NNT-80-
0033).(PYRIPROXYFEN), DACO: 4.5.2
1169747 1994, SUPPLEMENTAL DATA AND REVIEW OF ONCOGENICITY STUDY
WITH S-31183 (SUMILARV) IN MICE., DACO: 4.4.2
2704558 1994, AMENDMENTS 1 & 2 TO THE FINAL REPORT: SUMILARV -
COMBINED CHRONIC TOXICITY AND ONCOGENICITY STUDY IN RATS
WITH S-31183, MRID NO. 42178314 (original study), DACO: 4.4.4
2704559 1994, ADDENDUM TO THE FINAL REPORT: SUMILARV - COMBINED
CHRONIC TOXICITY AND ONCOGENICITY STUDY IN RATS WITH S-
31183 MRID NO 42178314, DACO: 4.4.4
References
Proposed Re-evaluation Decision - PRVD2019-10
Page 69
PMRA
Document
Number
Reference
2704560 1993, S-31183: TOXICITY STUDY BY ORAL (CAPSULE)
ADMINISTRATION TO BEAGLE DOGS FOR 52 WEEKS (ADDITIONAL
INVESTIGATION) / WITH THE FOLLOWING ATTACHED:
PYRIPROXYFEN/ DOG CHRONIC STUDY / TRANSMITTAL LETTER TO
C.I. TELLONE, VALENT, FROM T. KUMAGAI, SUMITOMO CHEMICAL
(MAR 22, 1995), DACO: 4.4.5
2704561 1994, AMENDMENT TO FINAL REPORT: ONCOGENICITY STUDY IN
MICE WITH S-31183 (SUMILARV) MRID NO. 42178310), DACO: 4.4.3
2704562 1993, METABOLISM OF [PYRIDYL-2,6-14C] PYRIPROXYFEN IN RATS,
DACO: 4.5.9
2704564 1992, SUMILARV - ACUTE INHALATION TOXICITY OF S-31183 IN RATS
SUPPLEMENTAL DATA SUPPLEMENT TO MRID # 42178304, DACO: 4.2.3
2704568 1993, ACUTE ORAL TOXICITY STUDY OF PYRIPROXYFEN
METABOLITES, 4-OH-PYR, 5-OH-PYR, DPH-PYR, POPA AND PYPAC, IN
MICE, DACO: 4.2.1
2704569 1996, Acute oral toxicity study of 2,5-OH-PY in mice, DACO: 4.2.1
2704570 1996, Acute oral toxicity study of 2-OH-PY in mice, DACO: 4.2.1
2704573 1995, REVERSE MUTATION TEST OF 2,5-OH-PY IN BACTERIAL
SYSTEMS, DACO: 4.5.4
2704574 1993, Reverse Mutation Test of Metabolites of Pyriproxyfen, 4-OH-PYR, 5-OH-
PYR, DPH-PYR, POPA AND PYPAC, in Bacterial Systems, DACO: 4.5.4
2704575 1995, Reverse mutation test of 2-OH-PY in bacterial systems, DACO: 4.5.4
2704576 1988, Two-Week Administration Study of S-31183 in Rabbits / English Version
from Japanese Original, DACO: 4.3.8
2704580 1988, Perinatal and postnatal study of S-31183 orally administered to rats /
English translation by A. Hirohashi, Sumitomo Chemical (Jan 12, 1993), DACO:
4.5.2
2704582 1988, Study by orally administration of S-31183 to rats prior to and in the early
stages of pregnancy / English translation by A. Hirohashi, Sumitomo Chemical
(Jan 22, 1993), DACO: 4.5.2
2704584 2005, Uterotropic Assay of Pyriproxyfen by Oral Route Using Juvenile Rat:
Investigation on Estrogenic Effect, DACO: 4.8
2704592 2011, Pyriproxyfen: Preliminary 4 Week Dietary Study in the Female CD-1
Mouse, DACO: 4.3.3
References
Proposed Re-evaluation Decision - PRVD2019-10
Page 70
PMRA
Document
Number
Reference
2704593 2011, Pyriproxyfen: 4 Week Dietary Immunotoxicity Study in the Female CD-1
Mouse, DACO: 4.5.15,870.78
2704596 2011, An Oral (Gavage) Dose Range-Finding Acute Neurotoxicity Study of
Pyriproxyfen T.G. in Rats, DACO: 4.5.12
2704597
2011, Hershberger Assay of Pyriproxyfen T.G. Administered Orally in Male Rats,
DACO: 4.8
2704598 2011, In vitro Inhibition Assay of Pyriproxyfen T.G. with Human Recombinant
Aromatase, DACO: 4.8
2704599 2011, In vitro Androgen Receptor Binding Assay of Pyriproxyfen T.G. with Rat
Prostate Cytosol, DACO: 4.8
2704600 2011, In vitro Steroidogenesis Assay of Pyriproxyfen T.G. with H295R Cell Line,
DACO: 4.8
2704601 2011, In vitro Estrogen Receptor Binding Assay of Pyriproxyfen T.G. with Rat
Uterine Cytosol, DACO: 4.8
2704602 2012, A Pubertal Development and Thyroid Function Assay of Pyriproxyfen T.G.
Administered Orally in Intact Juvenile/Peripubertal Female Rats, DACO: 4.8
2704603 2012, A Weight-of-Evidence of the EDSP Tier 1 Studies of Pyriproxyfen T.G.,
DACO: 4.8
2704604 2012, Effects of Pyriproxyfen on Testosterone Level and Thyroid Gland in Intact
Juvenile/Peripubertal Male Rats, DACO: 4.8
2704605 2012, A Pubertal Development and Thyroid Function Assay of Pyriproxyfen T.G.
Administered Orally in in Intact Juvenile/Peripubertal Male Rats, DACO: 4.8
2704606 2011, A 28-Day Dietary Dose Range-Finding Subchronic Neurotoxicity Study of
Pyriproxyfen T.G. in Rats, DACO: 4.5.13
2704607 2011, An Oral (Gavage) Acute Neurotoxicity Study of Pyriproxyfen T.G. in Rats,
DACO: 4.5.12
2704608 2011, A 90-Day Oral Dietary Neurotoxicity Study of Pyriproxyfen T.G. in Rats,
DACO: 4.5.13
References
Proposed Re-evaluation Decision - PRVD2019-10
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B. Additional Information Considered
i) Published Information
2.0 Human and Animal Health
PMRA
Document
Number
Reference
2831624
Bayoumi, A.E. et al, 2003, Cytotoxic effects of two antimolting insecticides
in mammalian CHO-K1 cells - Ecotoxicology and Environmental Safety,
Volume 55, Pages 19 to 23, DACO: 4.8
2831625
Kojima, Mihoko et al, 2005, Evaluation of estrogenic activities of pesticides
using an in vitro reporter gene assay - International Journal of Environmental
Health Research, Volume 15, Number 4, Pages 271 to 280, DACO: 4.8
2831626
Lamberti, Monica et al, 2014, Effects of Pyriproxyfen on Viability and
Increase of Intracellular Lipids in HepG2 Cell Line - Occupational Medicine
and Health Affairs, Volume 2, Issue 5, , DACO: 4.8
2831627
Manabe, Mari et al, 2006, Evaluation of the estrogenic activities of some
pesticides and their combinations using MtT/Se cell proliferation assay -
International Journal of Hygiene and Environmental Health, Volume 209,
Pages 413 to 421, DACO: 4.8
2857240
Thalia Velho Barreto de Araujo et al, 2017, Association between
microcephaly, Zika virus infection, and other risk factors in Brazil: final
report of a case-control study - The Lancet Infectious Diseases, Volume 18,
Number 3, Pages 328 to 336, DACO: 4.8
2857241
Raphael Parens et al, 2017, A Possible Link Between Pyriproxyfen and
Microcephaly - PLOS Currents Outbreaks. 2017 Nov 27 . Edition 1, DACO:
4.8
2857242
Maria de Fatima et al, 2016, Pyriproxyfen and the microcephaly epidemic in
Brazil - an ecological approach to explore the hypothesis of their association
- memorias do Instituto Oswaldo Cruz - Volume 111, Number 12, Pages 774
to 776, DACO: 4.8
2857243
Stefania Dzieciolowska et al, 2017, The larvicide pyriproxyfen blamed
during the Zika virus outbreak does not cause microcephaly in zebrafish
embryos - Scientific Reports volume 7, Article number: 40067 , DACO: 4.8
2857244
European Food Safety Authority, 2009, CONCLUSION ON PESTICIDE
PEER REVIEW Peer review of the pesticide risk assessment of the active
substance pyriproxyfen1 (Question No EFSA-Q-2009-00239) Issued on 21
July 2009, DACO: 12.5
2857245
United States Environmental Protection Agency, 2015, EDSP Weight of
Evidence Conclusions on the Tier 1 Screening Assays for the List 1
Chemicals, DACO: 12.5
References
Proposed Re-evaluation Decision - PRVD2019-10
Page 72
PMRA
Document
Number
Reference
2857246
United States Environmental Protection Agency, 2017, Pyriproxyfen. Human
Health Draft Risk Assessment for Registration Review., DACO: 12.5
2857247
United States Environmental Protection Agency, 2015, Pyriproxyfen. Human
Health Risk Assessment for the Petition to Increase the Established
Tolerance in/on Tea with a U.S. Registration for Imported Pyriproxyfen
treated Tea., DACO: 12.5
Information Considered for the Dietary Exposure and Risk Assessment
A. Additional Information Considered
i) Published Information
PMRA
Document
Number
Reference
1298193
PRDD2006-04: Pyriproxyfen, September 12, 2006.
2806584
REV2017-05: Re-evaluation Project Plan for Pyriproxyfen.
2956349
US EPA Memo: Pyriproxyfen. Dietary (Food and Drinking Water) Exposure and Risk
Assessment for Registration Review, DP# 440973, August 24, 2017.
2956279
EFSA: Reasoned opinion on the modification of the existing maximum residue level
for pyriproxyfen in bananas. EFSA Journal 2016;14(2):4387, 18 pp.
doi:10.2903/j.efsa.2016.4387.
2956357
JMPR 1999: Pyriproxyfen Evaluation.
Information Considered in the Occupational and Residential Assessment
A. Studies/Information Provided by Task Forces
PMRA
Document
Number
Reference
2115788
Agricultural Reentry Task Forces (ARTF). 2008. Data Submitted by the ARTF to
Support Revision of Agricultural Transfer Coefficients. Submission #2006-0257.
References
Proposed Re-evaluation Decision - PRVD2019-10
Page 73
B. Additional Information Considered
i) Unpublished Information
PMRA
Document
Number
Reference
2449137
Krolski, M.E., 2014. Observational Study to Determine Dermal and Inhalation
Exposure to Pest Control Operator (PCO) Workers Applying Deltamethrin and/or β-
Cyfluthrin Using Hand-held Equipment in a Crack and Crevice Application. SynTech
Research Laboratory Services Stilwell, KS & Eurofins Agrosciences Services, Inc.,
GA. Bayer Report No. RGDAY016. Unpublished.
C. USEPA Residential SOPs
PMRA
Document
Number
Reference
2409268
U.S. EPA (2012a). Standard Operating Procedures for Residential
Pesticide Exposure Assessment. EPA: Washington, DC. Revised
October 2012. Section 7.
Information Considered in the Environmental Assessment
A. Additional Information Considered
Published Information
PMRA
Document
Number
Reference
1298193
PRDD2006-04: Proposed Registration Decision Pyriproxyfen
1349295
RD2007-03: Registration Decision Pyriproxyfen